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Samuels A, Irie K, Mizuno T, Reifenberg J, Punt N, Vinks AA, Minar P. Integrating early response biomarkers in pharmacokinetic models: A novel method to individualize the initial infliximab dose in patients with Crohn's disease. Clin Transl Sci 2025; 18:e70086. [PMID: 39985779 PMCID: PMC11846607 DOI: 10.1111/cts.70086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/10/2024] [Accepted: 11/05/2024] [Indexed: 02/24/2025] Open
Abstract
The use of model-informed precision dosing to personalize infliximab has been shown to improve both the acquisition of concentration targets and clinical outcomes during maintenance. Current iterations of infliximab pharmacokinetic models include time-varying covariates of drug clearance, however, not accounting for the expected improvements in the covariates can lead to indiscriminate use of higher infliximab doses and imprecise drug exposure. The aim was to identify changes in the four biomarkers associated with infliximab clearance (Xiong et al. model) and determine if integration of these dynamic changes would improve model performance during induction and early maintenance. We analyzed two cohorts of children receiving infliximab for Crohn's Disease. The Emax method was used to assess time-varying changes in covariates. Model performance (observed vs. predicted infliximab concentrations) was evaluated using median percentage error (bias) and median absolute percentage error (precision). The combined cohorts included 239 Crohn's disease patients. We found from baseline to dose 4, the maximum changes in weight, albumin, erythrocyte sedimentation rate, and neutrophil CD64 were 4.7%, +11.7%, -62.4%, and -26.5%, respectively. We also found the use of baseline covariates alone to forecast future trough concentration was inferior to the Emax time-varying method with a significant improvement observed in bias (doses 2, 3, and 4) and precision (doses 2 and 4). The integration of the four time-varying biomarkers of drug clearance with pharmacokinetic modeling improved the accuracy and precision of the predictions. This novel strategy may be key to improving drug exposure, minimizing indiscriminate dosing strategies, and reducing healthcare costs.
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Affiliation(s)
- Abigail Samuels
- Department of Internal Medicine, Department of Veterans AffairsUniversity of Cincinnati School of MedicineCincinnatiOhioUSA
| | - Kei Irie
- Division of Translational and Clinical PharmacologyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Tomoyuki Mizuno
- Division of Translational and Clinical PharmacologyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Jack Reifenberg
- University of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Nieko Punt
- MedimaticsMaastrichtThe Netherlands
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Alexander A. Vinks
- Division of Translational and Clinical PharmacologyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Phillip Minar
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
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Dupenloup P, Zhou M, Dizon MP, Shah AP, Goldhaber-Fiebert JD, Owens DK, Streett SE, Brandeau ML, Barber GE. Therapeutic Drug Monitoring in Patients with Ulcerative Colitis on Infliximab: A Cost-Effectiveness Analysis. Dig Dis Sci 2025; 70:728-737. [PMID: 39724469 DOI: 10.1007/s10620-024-08802-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND AND AIMS Ulcerative colitis (UC) can be treated with infliximab (IFX). Therapeutic drug monitoring (TDM) can yield superior outcomes, but its cost-effectiveness is unknown. METHODS We used a decision analytic Markov model to conduct a cost-effectiveness analysis comparing proactive TDM, reactive TDM, no TDM, and combinations of proactive and reactive TDM in 25-year-old patients with UC started on IFX. Under proactive TDM, IFX concentration and anti-drug antibodies were measured every 6 months and during a flare; under reactive TDM, these were only measured during a flare. Patients with flares experienced decreased quality of life (QoL) and risked further complications. We evaluated lifetime costs (2021 U.S. dollars), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios, all discounted at 3% annually, from a healthcare sector perspective. We performed probabilistic sensitivity analysis (PSA) and deterministic sensitivity analyses. We used a willingness-to-pay threshold of $100,000 per QALY gained. RESULTS All TDM strategies increased QALYs and healthcare costs. Compared to no TDM, reactive TDM increased costs from $496,700 to $497,500 ($3,200 per QALY gained). 1 year of proactive TDM followed by reactive TDM increased costs to $508,600 ($63,800 per QALY gained relative to reactive TDM). In 46% of PSA samples, 1 year of proactive TDM followed by reactive TDM was most likely to be the optimal strategy. This strategy was less likely to be cost-effective when remission QoL was lower and when post-surgical QoL was higher. CONCLUSION 1 year of proactive TDM followed by reactive TDM is cost-effective in patients with UC on IFX.
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Affiliation(s)
- Paul Dupenloup
- Department of Management Science and Engineering, Huang Engineering Center, Stanford University, 475 Via Ortega, Mail Code: 4026, Stanford, CA, 94305, USA.
| | - Margaret Zhou
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthew P Dizon
- Department of Health Policy, Stanford University School of Medicine, Stanford, CA, USA
| | - Aadit P Shah
- Stanford University School of Medicine, Stanford, CA, USA
| | - Jeremy D Goldhaber-Fiebert
- Department of Health Policy, Stanford University School of Medicine, Stanford, CA, USA
- Center for Health Policy, Freeman Spogli Institute, Stanford University, Stanford, CA, USA
| | - Douglas K Owens
- Department of Health Policy, Stanford University School of Medicine, Stanford, CA, USA
- Center for Health Policy, Freeman Spogli Institute, Stanford University, Stanford, CA, USA
| | - Sarah E Streett
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Margaret L Brandeau
- Department of Management Science and Engineering, Huang Engineering Center, Stanford University, 475 Via Ortega, Mail Code: 4026, Stanford, CA, 94305, USA
| | - Grant E Barber
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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Hong SN, Song JH, Kim SJ, Park YH, Choi CW, Kim JE, Kim ER, Chang DK, Kim YH. Subcutaneous Infliximab Concentration Thresholds for Mucosal and Transmural Healing in Patients With Crohn's Disease. Aliment Pharmacol Ther 2025; 61:313-322. [PMID: 39552401 DOI: 10.1111/apt.18354] [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: 05/22/2024] [Revised: 06/09/2024] [Accepted: 10/09/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Predose trough concentrations (Ctrough) of intravenous infliximab (IV-IFX) during maintenance therapy are associated with therapeutic outcomes in patients with Crohn's disease (CD). A subcutaneous formulation of infliximab (SC-IFX) has shown high Ctrough values due to its favourable pharmacokinetics. AIMS To evaluate the association of Ctrough of SC-IFX with therapeutic outcomes and the threshold of SC-IFX Ctrough for achieving mucosal healing (MH) and transmural healing (TH) in patients with CD. METHODS We performed this cross-sectional study in patients with CD who had received SC-IFX maintenance therapy for ≥ 6 months. We measured SC-IFX Ctrough immediately before SC-IFX injection. We performed ileocolonoscopy/single-balloon enteroscopy and/or magnetic resonance enterography within 3 months of SC-IFX Ctrough measurement. MH was defined as SES-CD-ulcerated surface subscore of 0. TH was defined as simplified MaRIA score of 0. RESULTS We enrolled 124 patients with MH in 77.9% (74/95) and TH in 36.3% (37/102). SC-IFX Ctrough was significantly higher in patients with MH (24.1 vs.16.9 μg/mL; p = 0.001) and TH (26.0 vs. 20.5 μg/mL; p = 0.007) than in those without. ROC analysis identified that the threshold of SC-IFX Ctrough for MH and TH were 17.5 and 30.3 μg/mL, respectively. Multivariate logistic regression showed that SC-IFX Ctrough was significantly associated with MH (OR 1.16; 95% CI 1.05-1.27; p = 0.002) and TH (OR 1.08; 95% CI 1.02-1.14; p = 0.005). CONCLUSIONS SC-IFX Ctrough was positively associated with MH (≥ 18 μg/mL) and TH (≥ 30 μg/mL) in patients with CD, which may guide treatment decisions to optimise therapeutic response in the era of treat-to-target.
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Affiliation(s)
- Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joo Hye Song
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Jin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Ha Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chang Wan Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Eun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Fernandes SR, Bernardo S, Saraiva S, Rita Gonçalves A, Moura Santos P, Valente A, Araújo Correia L, Cortez-Pinto H, Magro F. Proactive Infliximab Monitoring Improves the Rates of Transmural Remission in Crohn's Disease: A Propensity Score-Matched Analysis. Inflamm Bowel Dis 2024; 30:1974-1982. [PMID: 37982426 DOI: 10.1093/ibd/izad272] [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: 08/03/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Few patients can reach transmural remission in Crohn's disease (CD) with currently available therapies. Proactive optimization of infliximab (IFX) based on trough levels may potentially improve these results. METHODS Retrospective cohort study including consecutive CD patients starting treatment with IFX. Rates of transmural remission were compared between patients with and without therapeutic drug monitoring (target level: 5-7 µg/mL). A propensity score-matched analysis was performed to adjust for potential confounders. RESULTS A total of 195 CD patients were included, 57.9% receiving proactive therapeutic drug monitoring. The rates of transmural remission were higher in patients under proactive therapeutic drug monitoring (37.2% vs 18.3%; P = .004) with similar results in the propensity score-matched analysis (34.2% vs 17.1%; P = .025). In multivariate analysis, proactive therapeutic drug monitoring was independently associated with transmural remission (odds ratio, 2.95; 95% confidence interval, 1.44-6.06; P = .003). CONCLUSIONS Proactive optimization of IFX based on trough levels increases the rates of transmural remission in CD.
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Affiliation(s)
- Samuel Raimundo Fernandes
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Sónia Bernardo
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Sofia Saraiva
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Ana Rita Gonçalves
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Paula Moura Santos
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Ana Valente
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
| | - Luís Araújo Correia
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
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Hu Y, Song Z, Gao Y, Jiang D, Ran Y, Ma Y, Li H, Zhao R. Is therapeutic drug monitoring a dancing partner for TNF-α inhibitors in real-world practice? Answers from an updated systematic review and meta-analysis. Expert Rev Clin Pharmacol 2024:1-14. [PMID: 39305187 DOI: 10.1080/17512433.2024.2403641] [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: 04/15/2024] [Accepted: 09/09/2024] [Indexed: 10/11/2024]
Abstract
INTRODUCTION This systematic review aimed to determine the effect of therapeutic drug monitoring (TDM) for tumor necrosis factor-α inhibitors (TNF-αI) in immune-mediated inflammatory diseases (IMIDs) based on real-world evidence, as results from published meta-analyses based on randomized controlled trials (RCTs) may not fully capture the nuances of clinical practice due to strict criteria. METHODS We searched PubMed, Embase, and the Cochrane Library up to 1 August 2023. Cohort studies comparing TDM (proactive and reactive) with empirical management were included. Primary outcome was effectiveness [for IBDs: clinical remission; for rheumatic diseases: clinical remission or low disease activity], with certainty of evidence appraised using the GRADE approach. Secondary outcomes included treatment failure, serious adverse events (SAEs), IMIDs-related surgeries or hospitalizations, and anti-drug antibodies (ADAs) development risk. RESULTS Twenty-four cohort studies were included and almost all were on infliximab. For IBDs, compared with empirical management, proactive TDM significantly improved clinical remission (RR = 1.15, 95% CI = 1.04-1.28), reduced IBDs-related surgeries (RR = 0.46, 95% CI = 0.26-0.81), hospitalizations (RR = 0.60, 95% CI = 0.43-0.83), SAEs (RR = 0.23, 95% CI = 0.07-0.76), and ADAs development risk (RR = 0.34, 95% CI = 0.19-0.60). Reactive TDM significantly lowered hospitalization rates and might be cost-effective. Proactive TDM outperformed reactive TDM in secondary outcomes. For rheumatic diseases, benefits of TDM were inconclusive due to limited evidence. CONCLUSIONS Real-world evidence supports proactive TDM of TNF-αI (particularly infliximab) in IBDs to improve effectiveness, safety, and immunogenicity. However, benefits of TDM for different TNF-αI in other IMIDs remain uncertain. PROTOCOL REGISTRATION www.crd.york.ac.uk/ PROSPERO identifier is CRD42022370846.
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Affiliation(s)
- Yang Hu
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Zaiwei Song
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Yuan Gao
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Dan Jiang
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yiwen Ran
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yi Ma
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Huibo Li
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Rongsheng Zhao
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
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Marshanski T, Fanous E, Tal N, Perets TT, Matar M, Weintraub Y, Shamir R, Shouval DS. Different infliximab induction dosing regimens do not affect remission rates up to 1 year in children with Crohn's disease. J Pediatr Gastroenterol Nutr 2024; 79:564-572. [PMID: 38979682 DOI: 10.1002/jpn3.12307] [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: 12/09/2023] [Revised: 05/29/2024] [Accepted: 06/22/2024] [Indexed: 07/10/2024]
Abstract
OBJECTIVES Multiple studies in patients with Crohn's disease (CD) treated with anti-tumor necrosis factor alpha agents have shown that proactive therapeutic drug monitoring (TDM) during the maintenance phase leads to improved outcomes. We aimed to assess whether accelerated (IFX) administration during induction resulted in improved outcomes. METHODS This retrospective study included CD patients aged 5-17.9 years that were treated with IFX. We compared outcomes of patients treated during induction with 5-8 mg/kg dosing at Weeks 0, 2, 6, and 14 (Group 1), versus accelerated dosing (≥8 mg/kg and/or >4 infusions until Week 14, Group 2) of IFX. Primary outcome was steroid-free clinical remission by Week 52. RESULTS Sixty-eight patients were included, of whom seven discontinued IFX before Week 14, due to infusion reactions, immunogenic failure, or primary nonresponse. Comparison of Group 1 (n = 25) and Group 2 (n = 36) showed similar clinical characteristics, as well as inflammatory markers, at IFX initiation. Despite receiving significantly more IFX, and reaching a higher trough level by Week 14 (10.3 ± 1.2 vs. 3.3 ± 0.7, p < 0.001), the median Pediatric Crohn's disease Activity Index (PCDAI) was slightly higher in Group 2 versus Group 1 (14 [5-20] vs. 5 [0-15], p = 0.02). However, at Weeks 26 and 52 the PCDAI and inflammatory markers were comparable between the groups. Moreover, about 70% in both groups achieved the desirable trough IFX levels by Week 52. CONCLUSION Accelerated IFX dosing during induction did not result in improved outcomes up to 12 months follow-up. Prospective studies are required to determine the exact timing in which proactive TDM should be applied.
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Affiliation(s)
- Tal Marshanski
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Eliana Fanous
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Noa Tal
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tsachi T Perets
- Gastroenterology Laboratory, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
- Department of Digital Medical Technologies, Holon Institute of Technology, Holon, Israel
| | - Manar Matar
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Weintraub
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dror S Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Kim ES, Chon H, Kwon Y, Lee M, Kim MJ, Choe YH. Fluorescence-Based Lateral Flow Immunoassay for Quantification of Infliximab: Analytical and Clinical Performance Evaluation. Ther Drug Monit 2024; 46:460-467. [PMID: 38287890 PMCID: PMC11232936 DOI: 10.1097/ftd.0000000000001176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/15/2023] [Indexed: 01/31/2024]
Abstract
BACKGROUND Therapeutic drug monitoring of infliximab (IFX) can improve treatment outcomes; however, the temporal gap between drug concentration monitoring and subsequent availability restricts its practical application. To address this issue, an automated monitoring method, AFIAS IFX, was developed to rapidly and accurately analyze IFX concentration in blood. The analytical and clinical performances of this method were assessed to establish its clinical utility. METHODS The analytical performance of AFIAS IFX was evaluated according to Clinical and Laboratory Standard Institute guidelines. For clinical validation, AFIAS IFX was compared with 3 established enzyme-linked immunosorbent assay kits (LISA TRACKER, RIDASCREEN, and ImmunoGuide) using 100 consecutive samples from 28 patients treated with IFX. Passing-Bablok regression and Bland-Altman analyses were performed to compare the methods. RESULTS The detection and quantification limits of AFIAS IFX were 0.12 and 0.20 mcg/mL, respectively. Furthermore, AFIAS IFX analyzed samples within 10 minutes for concentrations up to 50 mcg/mL, exhibiting reproducibility (coefficient of variation [CV] ≤7.8%) and accuracy (recovery 98%-101%) with serum, plasma, and whole blood samples. Clinically, it exhibited a good correlation with the 3 established enzyme-linked immunosorbent assay kits. For patients treated with Remicade (IFX), the Passing-Bablok regression slope was 1.001-1.259, with a mean difference of -1.48 to 0.28 mcg/mL. For patients treated with CT-P13, the Passing-Bablok regression slope was 0.974-1.254, with a mean difference of -2.44 to 0.15 mcg/mL. CONCLUSIONS AFIAS IFX, a novel fluorescence-based lateral flow assay, exhibited excellent performance in analyzing IFX trough levels and is a potentially powerful tool for therapeutic drug monitoring in clinical settings, with opportunities for further development.
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Affiliation(s)
- Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea
| | - Hyangah Chon
- Department of R&D, Boditech Med Inc., Gangwon-do, Republic of Korea; and
| | - Yiyoung Kwon
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea
- Department of Pediatrics, Inha University School of Medicine, Inha University Hospital, Incheon, Republic of Korea
| | - Misook Lee
- Department of R&D, Boditech Med Inc., Gangwon-do, Republic of Korea; and
| | - Mi Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea
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Wang W, Zhang Q, Zhao J, Liu T, Yao J, Peng X, Zhi M, Zhang M. HLA-DQA1*05 correlates with increased risk of anti-drug antibody development and reduced response to infliximab in Chinese patients with Crohn's disease. Gastroenterol Rep (Oxf) 2024; 12:goae074. [PMID: 39055374 PMCID: PMC11269678 DOI: 10.1093/gastro/goae074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 03/30/2024] [Accepted: 05/07/2024] [Indexed: 07/27/2024] Open
Abstract
Background The efficacy of anti-TNF therapy in Crohn's disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes. Methods In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A > G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals. Results A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLA-DQA1*05 wild-type carriers (58.5% vs 42.9%, P = 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio = 1.65, 95% CI 1.18-2.30, P = 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR = 2.55, 95% CI 1.78-3.68, P < 0.0001) and treatment discontinuation (adjusted HR = 2.21, 95% CI 1.59-3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers. Conclusions HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.
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Affiliation(s)
- Wei Wang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Qi Zhang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Junzhang Zhao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Tao Liu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Jiayin Yao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Xiang Peng
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Min Zhi
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
| | - Min Zhang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510655, P. R. China
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9
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Gomes LEM, Genaro LM, de Castro MM, Ricci RL, Pascoal LB, Silva FBC, Bonfitto PHL, Camargo MG, Corona LP, Ayrizono MDLS, de Azevedo AT, Leal RF. Infliximab monitoring in Crohn's disease: a neural network approach for evaluating disease activity and immunogenicity. Therap Adv Gastroenterol 2024; 17:17562848241251949. [PMID: 39664232 PMCID: PMC11632880 DOI: 10.1177/17562848241251949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 04/15/2024] [Indexed: 12/13/2024] Open
Abstract
Background The treatment for Crohn's disease (CD) has increasingly required the use of biological agents. Safe and affordable tests have led to the active implementation of therapeutic drug monitoring (TDM) in clinical practice, which, although not yet widely available across all health services, has been proven effective. Objective To analyze serum infliximab (IFX) and antidrug antibody (ADA) levels in CD patients, compare two tests, as well as construct a prediction of neural network using a combination of clinical, epidemiological, and laboratory variables. Design Cross-sectional observational study. Method A cross-sectional observational study was conducted on 75 CD patients in the maintenance phase of IFX treatment. The participants were allocated into two groups: CD in activity (CDA) and in remission (CDR). Disease activity was defined by endoscopic or radiological criteria. Serum IFX levels were measured by enzyme-linked immunosorbent assay (ELISA) and rapid lateral flow assay; ADA levels were measured by ELISA. A nonparametric test was used for statistical analysis; p value of ⩽0.05 was considered significant. Differences between ELISA and rapid lateral flow results within the measurement range were assessed by the Wilcoxon test, Passing-Bablok regression, and Bland-Altman method. Prediction models were created using four neural network sets. Neural networks and performance receiver operating characteristic curves were created using the Keras package in Python software. Results Most participants exhibited supratherapeutic IFX levels (>7 mg/mL). Both tests showed no difference in IFX levels between the CDA and CDR groups (p > 0.05). The use of immunosuppressive therapy did not affect IFX levels (p > 0.05). Only 14.66% of patients had ADA levels >5 AU/mL, and all ADA-positive participants exhibited subtherapeutic IFX levels in both tests. The median results of both tests showed significant differences and moderate agreement (r = -0.6758, p < 0.001). Of the four neural networks developed, two showed excellent performance, with area under the curve (AUCs) of 82-92% and 100%. Conclusion Most participants exhibited supratherapeutic IFX levels, with no significant serum level difference between the groups. There was moderate agreement between tests. Two neural network sets showed disease activity and the presence of ADA, noninvasively determined in patients using IFX by presenting an AUC of >80%.
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Affiliation(s)
- Luis Eduardo Miani Gomes
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Livia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Marina Moreira de Castro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Renato Lazarin Ricci
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Livia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Filipe Botto Crispim Silva
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Pedro Henrique Leite Bonfitto
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Michel Gardere Camargo
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Ligiana Pires Corona
- Nutritional Epidemiology Laboratory, School of Applied Sciences, University of Campinas, Limeira, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Anibal Tavares de Azevedo
- Simulation Laboratory, School of Applied Sciences, University of Campinas, Limeira, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Carlos Chagas Street, 420, Cidade Universitária Zeferino Vaz, Campinas 13083-878, São Paulo, Brazil
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10
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Rowland P, McNicol M, Kiel A, Maltz RM, Donegan A, Dotson JL, Michel HK, Boyle B. Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 78:853-861. [PMID: 38270212 DOI: 10.1002/jpn3.12132] [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: 07/07/2023] [Revised: 12/12/2023] [Accepted: 01/03/2024] [Indexed: 01/26/2024]
Abstract
OBJECTIVES Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). METHODS A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 μg/mL at Week 6 and >12 μg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. RESULTS Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6 and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 μg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR) rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). CONCLUSION Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.
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Affiliation(s)
- Patrick Rowland
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Megan McNicol
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pharmacy, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Ashley Kiel
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Ross M Maltz
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
- The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Amy Donegan
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Jennifer L Dotson
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pharmacy, Nationwide Children's Hospital, Columbus, Ohio, USA
- Center for Child Health Equity and Outcomes Research, Columbus, Ohio, USA
| | - Hilary K Michel
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pharmacy, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Brendan Boyle
- Division of Gastroenterology and Hepatology, Nationwide Children's Hospital, Columbus, Ohio, USA
- The Ohio State University College of Medicine, Columbus, Ohio, USA
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11
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Minar PP, Colman RJ, Zhang N, Mizuno T, Vinks AA. Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn's disease (REMODEL-CD): study protocol for a multicentre, open-label, pragmatic clinical trial in the USA. BMJ Open 2024; 14:e077193. [PMID: 38531570 PMCID: PMC10966820 DOI: 10.1136/bmjopen-2023-077193] [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: 06/27/2023] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
INTRODUCTION The only biologic therapy currently approved to treat moderate to severe Crohn's disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically important to develop novel strategies that maximise treatment effectiveness in this population. There is growing evidence that rates of sustained corticosteroid-free clinical remission, endoscopic healing and drug durability considerably improve when patients receive early anti-TNF dose optimisations guided by reactive or proactive therapeutic drug monitoring and pharmacodynamic monitoring. In response, our team has developed a personalised and scalable infliximab dosing intervention that starts with dose selection and continues throughout maintenance to optimise drug exposure. We hypothesise that a precision dosing strategy starting from induction and targeting dose-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy will significantly improve outcomes compared with a conventional dosing strategy. METHODS AND ANALYSIS Conduct a clinical trial to assess rates of deep remission between Crohn's disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6-22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5-10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn's disease activity index<10 (child) or a Crohn's disease activity index<150 (adults)), off prednisone>8 weeks and endoscopic remission (simple endoscopic severity-Crohn's disease≤2). ETHICS AND DISSEMINATION ). The study protocol has been approved by the Cincinnati Children's Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER NCT05660746.
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Affiliation(s)
- Phillip Paul Minar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA
| | - Ruben J Colman
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Nanhua Zhang
- Division of Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Tomoyuki Mizuno
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alexander A Vinks
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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12
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Zheng FY, Yang KS, Min WC, Li XZ, Xing Y, Wang S, Zhang YS, Zhao QC. Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis. World J Gastrointest Surg 2024; 16:571-584. [PMID: 38463352 PMCID: PMC10921189 DOI: 10.4240/wjgs.v16.i2.571] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/14/2023] [Accepted: 01/16/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. AIM To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. METHODS As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. RESULTS This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). CONCLUSION Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.
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Affiliation(s)
- Fang-Yuan Zheng
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Kai-Si Yang
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Wen-Cheng Min
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Xin-Zhu Li
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Yu Xing
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Shuai Wang
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Ying-Shi Zhang
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Qing-Chun Zhao
- Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
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13
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Ansari M, Glassner K, Irani M, Saleh A, Wang L, Ezeana C, Wong S, Perry C, Abraham B. Therapeutic drug monitoring in inflammatory bowel disease patients on vedolizumab. J Dig Dis 2024; 25:91-99. [PMID: 38599667 DOI: 10.1111/1751-2980.13261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/16/2024] [Accepted: 02/27/2024] [Indexed: 04/12/2024]
Abstract
OBJECTIVE We aimed to investigate whether vedolizumab (VDZ) levels were associated with inflammatory markers or clinical or endoscopic scoring in inflammatory bowel disease (IBD). METHODS Besides demographic data, clinical scoring, endoscopic data, and laboratory markers of IBD patients treated with VDZ from 2015 to 2020 who had trough levels drawn on maintenance therapy were collected at baseline and at follow-up (after at least 8 weeks on VDZ therapy or after change in dose frequency). Low drug levels were defined as VDZ trough <20 μg/mL. RESULTS We identified 89 patients with a mean age of 42.9 years. Of the 90 total trough levels drawn, 61.1% were low. Among patients on every 8 week (Q8 week) VDZ dosing, 81.5% had low troughs. After increasing dosing frequency to Q4 weeks, all patients showed improvement in VDZ levels, but 30.6% remained <20 μg/mL. Higher VDZ levels on Q8 week dosing were associated with higher albumin levels (P = 0.01). While higher VDZ levels on Q4 week dosing were associated with higher albumin (P = 0.02), lower erythrocyte sedimentation rate (P = 0.04) and higher likelihood of having mild disease or endoscopic remission (P = 0.01). No significant association was found between VDZ levels and clinical scoring, body mass index, hemoglobin, vitamin D or platelet levels on either Q8 or Q4 week dosing. CONCLUSIONS Higher VDZ troughs were associated with higher albumin, mild endoscopic disease or endoscopic remission. Patients who continue to have low VDZ troughs despite Q4 week dosing may require a change in therapy.
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Affiliation(s)
- Mohammed Ansari
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Kerri Glassner
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Malcolm Irani
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Adam Saleh
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Lin Wang
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Chika Ezeana
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Stephen Wong
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Caroline Perry
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
| | - Bincy Abraham
- Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas, USA
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14
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Dutt K, Vasudevan A. Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:250. [PMID: 38399538 PMCID: PMC10890472 DOI: 10.3390/medicina60020250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024]
Abstract
Background: Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, necessitates long-term medical therapy to manage symptoms and prevent complications. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize treatment efficacy, particularly with anti-tumour necrosis factor (anti-TNF) alpha drugs. This review explores the role of TDM for non-anti-TNF advanced therapies in IBD, focusing on vedolizumab, ustekinumab, tofacitinib, upadacitinib, risankizumab and ozanimod. Methods: The literature search, conducted through OVID (Medline) and PubMed, delves into proactive versus reactive TDM, timing of monitoring and methods for measuring drug levels and anti-drug antibodies. Results: While ustekinumab and vedolizumab exhibit exposure-response relationships, consensus on target levels and the role of TDM adjustments remains elusive. Limited data on risankizumab suggest a dose-dependent response, while for small molecule therapies (janus kinase inhibitors and ozanimod), the absence of real-world data and commercially available TDM tools pose challenges. Conclusion: At present, with the available data, there is a limited role for TDM in non-anti-TNF biologic and small-molecule therapies. This review underscores the need for further research to delineate the utility of TDM in guiding treatment decisions for these agents.
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Affiliation(s)
- Krishneel Dutt
- Eastern Health, 8 Arnold Street, Box Hill, VIC 3128, Australia;
- Eastern Health Clinical School, Monash University, 8 Arnold Street, Box Hill, VIC 3128, Australia
| | - Abhinav Vasudevan
- Eastern Health, 8 Arnold Street, Box Hill, VIC 3128, Australia;
- Eastern Health Clinical School, Monash University, 8 Arnold Street, Box Hill, VIC 3128, Australia
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15
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Clinton JW, Cross RK. Personalized Treatment for Crohn's Disease: Current Approaches and Future Directions. Clin Exp Gastroenterol 2023; 16:249-276. [PMID: 38111516 PMCID: PMC10726957 DOI: 10.2147/ceg.s360248] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/04/2023] [Indexed: 12/20/2023] Open
Abstract
Crohn's disease is a complex, relapsing and remitting inflammatory disorder of the gastrointestinal tract with a variable disease course. While the treatment options for Crohn's disease have dramatically increased over the past two decades, predicting individual patient response to treatment remains a challenge. As a result, patients often cycle through multiple different therapies before finding an effective treatment which can lead to disease complications, increased costs, and decreased quality of life. Recently, there has been increased emphasis on personalized medicine in Crohn's disease to identify individual patients who require early advanced therapy to prevent complications of their disease. In this review, we summarize our current approach to management of Crohn's disease by identifying risk factors for severe or disabling disease and tailoring individual treatments to patient-specific goals. Lastly, we outline our knowledge gaps in implementing personalized Crohn's disease treatment and describe the future directions in precision medicine.
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Affiliation(s)
- Joseph William Clinton
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Raymond Keith Cross
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
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16
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Samuels A, Whaley KG, Minar P. Precision Dosing of Anti-TNF Therapy in Pediatric Inflammatory Bowel Disease. Curr Gastroenterol Rep 2023; 25:323-332. [PMID: 37695555 PMCID: PMC10865142 DOI: 10.1007/s11894-023-00895-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 09/12/2023]
Abstract
PURPOSE OF THE REVIEW This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD). RECENT FINDINGS Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5 µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.
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Affiliation(s)
- Abigail Samuels
- Department of Medicine, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, 5229, USA
| | - Kaitlin G Whaley
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Phillip Minar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Dubinsky MC, Rabizadeh S, Panetta JC, Spencer EA, Everts-van der Wind A, Dervieux T. The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab. Pharmaceutics 2023; 15:2408. [PMID: 37896168 PMCID: PMC10610097 DOI: 10.3390/pharmaceutics15102408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (p < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (p < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = -19.2; p < 0.001), and the combination of both further minimized OFV (p < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.
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Affiliation(s)
| | | | - John C. Panetta
- St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;
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West J, Tan K, Devi J, Macrae F, Christensen B, Segal JP. Benefits and Challenges of Treat-to-Target in Inflammatory Bowel Disease. J Clin Med 2023; 12:6292. [PMID: 37834936 PMCID: PMC10573216 DOI: 10.3390/jcm12196292] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
There is notable disparity between symptomatology and disease activity in a significant proportion of patients with inflammatory bowel disease (IBD), and escalation of treatment based on symptoms alone can fail to significantly alter the course of disease. The STRIDE-II position statement, published in 2021 by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organisation for the Study of IBD (IOIBD) provides the most current recommendations for a treat-to-target (T2T) approach in IBD. Despite the benefits offered by a T2T approach in IBD, there are numerous drawbacks and current limitations to its widespread implementation in real-world clinical practice. Owing to the lack of a standardised definition of MH, outcome data are heterogeneous and limit the comparability of existing data. Further, studies investigating the likelihood of achieving MH with a T2T approach are limited and largely retrospective. Evidence of the real-world feasibility of tight monitoring is currently minimal and demonstrates sub-optimal adherence among patients. Further, the few studies on the acceptability and uptake of a T2T approach in real-world practice demonstrate the need for increased acceptability on both patients' and clinicians' behalf. Real-world applicability is further limited by the need for repeated endoscopic assessments of MH as well as a lack of guidance on how to incorporate the various treatment targets into therapeutic decision-making. We aim to review the benefits and challenges of the T2T approach and to discuss potential solutions to further patient care.
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Affiliation(s)
- Jack West
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne 3052, Australia
| | - Katrina Tan
- Department of Gastroenterology, Northern Health, Epping, Melbourne 3076, Australia
| | - Jalpa Devi
- Department of Gastroenterology, Washington University in Saint Louis, St. Louis, MI 63110, USA
| | - Finlay Macrae
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne 3052, Australia
- The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Britt Christensen
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne 3052, Australia
- The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Jonathan P. Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne 3052, Australia
- The University of Melbourne, Parkville, Melbourne 3010, Australia
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Cheli S, Savino D, De Silvestri A, Norsa L, Sansotta N, Penagini F, Dilillo D, Panceri R, Cattaneo D, Clementi E, Zuin G. One year of experience with combined pharmacokinetic/pharmacogenetic monitoring of anti-TNF alpha agents: a retrospective study. THE PHARMACOGENOMICS JOURNAL 2023; 23:112-118. [PMID: 37016150 DOI: 10.1038/s41397-023-00304-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 04/06/2023]
Abstract
Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (-308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.
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Affiliation(s)
- Stefania Cheli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Diego Savino
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Annalisa De Silvestri
- Clinical Epidemiology and Biometry Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Lorenzo Norsa
- Pediatric Hepatology, Gastroenterology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Naire Sansotta
- Pediatric Hepatology, Gastroenterology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Francesca Penagini
- Pediatric Department, "Vittore Buzzi" Children's Hospital, University of Milan, Milano, Italy
| | - Dario Dilillo
- Pediatric Department, "Vittore Buzzi" Children's Hospital, University of Milan, Milano, Italy
| | - Roberto Panceri
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Emilio Clementi
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
- Clinical Pharmacology Unit, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy.
| | - Giovanna Zuin
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
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20
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Serrano-Díaz L, Iniesta-Navalón C, Gómez-Espín R, Nicolás-de Prado I, Bernal-Morell E, Rentero-Redondo L. Impact of proactive therapeutic drug monitoring of infliximab during the induction phase in IBD patients. A Bayesian approach. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:435-443. [PMID: 36562529 DOI: 10.17235/reed.2022.8781/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND OBJECTIVES there is increasing evidence that proactive therapeutic drug monitoring in induction is useful to improve the control of inflammatory bowel disease (IBD), although it remains controversial. The primary objective of the study was to assess the short-term outcomes of proactive Bayesian therapeutic drug monitoring (TDM) during induction, to optimize infliximab (IFX) maintenance dose. METHODS retrospective observational cohort of IBD patients > 18 years. They were divided into two cohorts, standard therapy group (ST-group), with clinically based dose adjustment, and monitoring group (iTDM-group), with pharmacokinetic parameters calculated by Bayesian prediction at week 6 and individualized dosage regimens thereafter. In patients with an infliximab trough level (ITL) at week 6 below the optimal therapeutic range, the dose adjustment was performed at the first maintenance dose. RESULTS a total of 153 patients were included, 40 in the iTDM-group. Median ITL at week 6 during the induction period was 12.8 µg/ml (IRQ: 12.7) in this group. Only 16 patients (40.0 %) had ITL ≥ 15 µg/ml. Half of the patients (50.3 %) received intensified maintenance therapy during the study period (57.5 % iTDM vs 47.8 % ST, p = 0.291). The proportion of patients achieving primary response at week 14 was 51.8 %. When comparing the two groups, this proportion was higher in the iTDM group (74.3 % vs 44.2 %, p = 0.002). With regards to the variable "poor clinical outcomes" at week 26, this proportion was lower in the iTDM group (3.3 % iTDM vs 21.1 % ST, p = 0.024). CONCLUSIONS proactive therapeutic drug monitoring using Bayesian approach is associated with higher primary response rates and fewer short-term complications.
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21
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Choi SY, Kwon Y, Choi S, Lee SM, Choe BH, Kang B. Infliximab trough levels are associated with endoscopic healing but not with transmural healing at one year treatment with infliximab in pediatric patients with Crohn's disease. Front Immunol 2023; 14:1192827. [PMID: 37426637 PMCID: PMC10326720 DOI: 10.3389/fimmu.2023.1192827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/12/2023] [Indexed: 07/11/2023] Open
Abstract
Introduction It is well known that infliximab (IFX) trough levels (TLs) are associated with endoscopic healing (EH) in Crohn's disease (CD). We investigated whether IFX TLs are associated with transmural healing (TH) in pediatric patients with CD following 1-year treatment. Methods Pediatric patients with CD treated with IFX were included in this single-center prospective study. IFX TL tests, magnetic resonance enterography (MRE), and colonoscopies were simultaneously conducted after 1-year IFX treatment. TH was defined as a wall thickness of ≤3 mm without inflammatory signs evaluated using MRE. EH was defined as a Simple Endoscopic Score for Crohn's disease of <3 points on colonoscopy. Results Fifty-six patients were included. EH and TH were observed in 60.7% (34/56) and 23.2% (13/56) of patients, respectively. IFX TLs were higher in patients with EH (median, 5.6 vs. 3.4 µg/mL, P = 0.002), whereas IFX TLs showed no significant difference in patients with and without TH (median, 5.4 vs. 4.7 µg/mL, P = 0.574). No significant difference was observed in EH and TH between patients whose intervals were shortened or not. Multivariate logistic regression analysis showed that IFX TLs and disease duration to IFX initiation were associated with EH (odds ratio [OR] = 1.82, P = 0.001, and OR = 0.43, P = 0.02, respectively). Discussion In pediatric patients with CD, IFX TLs were associated with EH but not with TH. Further studies investigating long-term TH and proactive dosing based on therapeutic drug monitoring may clarify whether an association between IFX TLs and TH exists.
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Affiliation(s)
- So Yoon Choi
- Department of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Yiyoung Kwon
- Department of Pediatrics, School of Medicine, Inha University, Incheon, Republic of Korea
| | - Sujin Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - So Mi Lee
- Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
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22
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Prokopič M, Gilca-Blanariux G, Lietava P, Trifan A, Pietrzak A, Ladic A, Brinar M, Turcan S, Molnár T, Bánovčin P, Lukáš M. Barriers in inflammatory bowel disease care in Central and Eastern Europe: a region-specific analysis. Therap Adv Gastroenterol 2023; 16:17562848231174290. [PMID: 37333465 PMCID: PMC10272651 DOI: 10.1177/17562848231174290] [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: 12/31/2022] [Accepted: 04/20/2023] [Indexed: 06/20/2023] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic immune-mediated diseases with a high incidence and prevalence in Europe. Since these are diseases with associated disability, they require complex management and the availability of high-quality healthcare resources. We focused on the analysis of IBD care in selected countries of Central and Eastern Europe (Croatia, the Czech Republic, Hungary, Moldova, Poland, Romania and Slovakia) targeting the availability and reimbursement of diagnostic and therapeutic modalities, the role of IBD centers and also education and research in IBD. As part of the analysis, we created a questionnaire of 73 statements organized in three topics: (1) diagnostics, follow-up and screening, (2) medications and (3) IBD centers. The questionnaire was filled out by co-authoring IBD experts from individual countries, and then the answers and comments on the questionnaire were analyzed. We identified that despite the financial burden, which still partially persists in the region, the availability of some of the cost-saving tools (calprotectin test, therapeutic drug monitoring) differs among countries, mainly due to variable reimbursement from country to country. In most participating countries, there also remains a lack of dedicated dietary and psychological counseling, which is often replaced by recommendations offered by gastroenterologists. However, there is adequate availability of most of the currently recommended diagnostic methods and therapies in each participating country, as well as the implementation of established IBD centers in the region.
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Affiliation(s)
| | | | - Peter Lietava
- Department of Gastroenterology, Jessenius Faculty of Medicine, Comenius University Bratislava, Martin, Slovakia
| | - Anca Trifan
- Department of Gastroenterology, Grigore T Popa University of Medicine and Pharmacy, Iasi, Romania
- Sf Spiridon County Clinical Emergency Hospital, Iasi, Romania
| | - Anna Pietrzak
- Second Gastroenterology Department, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Agata Ladic
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Marko Brinar
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Svetlana Turcan
- Department of Gastroenterology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Tamás Molnár
- First Department of Medicine, University of Szeged Faculty of Medicine, Szeged, Hungary
| | - Peter Bánovčin
- Department of Gastroenterology, Jessenius Faculty of Medicine, Comenius University Bratislava, Martin, Slovakia
| | - Milan Lukáš
- IBD Clinical and Research Center, ISCARE a.s. and the First Faculty of Medicine, Charles University, Prague, Czech Republic
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23
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Orfanoudaki E, Foteinogiannopoulou K, Theodoraki E, Koutroubakis IE. Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12072452. [PMID: 37048536 PMCID: PMC10095227 DOI: 10.3390/jcm12072452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.
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Affiliation(s)
- Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Kalliopi Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini Theodoraki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
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24
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Fuxman C, Sicilia B, Linares ME, García-López S, González Sueyro R, González-Lamac Y, Zabana Y, Hinojosa J, Barreiro-de Acosta M, Balderramo D, Balfour D, Bellicoso M, Daffra P, Morelli D, Orsi M, Rausch A, Ruffinengo O, Toro M, Sambuelli A, Novillo A, Gomollón F, De Paula JA. GADECCU 2022 Guideline for the treatment of Ulcerative Colitis. Adaptation and updating of the GETECCU 2020 Guideline. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46 Suppl 1:S1-S56. [PMID: 36731724 DOI: 10.1016/j.gastrohep.2023.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/04/2023] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Ulcerative colitis (UC) is a chronic inflammatory disease that compromises the colon, affecting the quality of life of individuals of any age. In practice, there is a wide spectrum of clinical situations. The advances made in the physio pathogenesis of UC have allowed the development of new, more effective and safer therapeutic agents. OBJECTIVES To update and expand the evaluation of the efficacy and safety of relevant treatments for remission induction and maintenance after a mild, moderate or severe flare of UC. RECIPIENTS Gastroenterologists, coloproctologists, general practitioners, family physicians and others health professionals, interested in the treatment of UC. METHODOLOGY GADECCU authorities obtained authorization from GETECCU to adapt and update the GETECCU 2020 Guide for the treatment of UC. Prepared with GRADE methodology. A team was formed that included authors, a panel of experts, a nurse and a patient, methodological experts, and external reviewers. GRADE methodology was used with the new information. RESULTS A 118-page document was prepared with the 44 GADECCU 2022 recommendations, for different clinical situations and therapeutic options, according to levels of evidence. A section was added with the new molecules that are about to be available. CONCLUSIONS This guideline has been made in order to facilitate decision-making regarding the treatment of UC, adapting and updating the guide prepared by GETECCU in the year 2020.
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Affiliation(s)
- Claudia Fuxman
- Servicio de Gastroenterología, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina.
| | - Beatriz Sicilia
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario de Burgos, Burgos, España
| | - María Eugenia Linares
- Servicio de Gastroenterología, Hospital de Clínicas José de San Martín, Buenos Aires, Argentina
| | - Santiago García-López
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, España
| | - Ramiro González Sueyro
- Servicio de Gastroenterología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Yago González-Lamac
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario Puerta de Hierro, Madrid, España
| | - Yamile Zabana
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario Mútua Terrassa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, España
| | - Joaquín Hinojosa
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital de Manise, Valencia, España
| | - Manuel Barreiro-de Acosta
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, España
| | - Domingo Balderramo
- Servicio de Gastroenterología, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
| | - Deborah Balfour
- Unidad de Enfermedades Inflamatorias, HIGEA Clínica de Gastroenterología, Mendoza, Argentina
| | - Maricel Bellicoso
- Área de Gastroenterología, Inmunología Buenos Aires, Buenos Aires, Argentina
| | - Pamela Daffra
- Servicio de Gastroenterología, Hospital Central de Mendoza, Mendoza, Argentina
| | - Daniela Morelli
- Departamento de Educación, Instituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina
| | - Marina Orsi
- Servicio de Gastroenterología Pediátrica, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Astrid Rausch
- Servicio de Gastroenterología, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
| | - Orlando Ruffinengo
- Servicio de Gastroenterología, Hospital Provincial del Centenario, Rosario, Argentina
| | - Martín Toro
- Unidad de Enfermedades Inflamatorias, HIGEA Clínica de Gastroenterología, Mendoza, Argentina
| | - Alicia Sambuelli
- Sección de Enfermedades Inflamatorias Intestinales, Hospital Bonorino Udaondo, Buenos Aires, Argentina
| | - Abel Novillo
- Servicio de Gastroenterología, Sanatorio 9 de Julio, Tucumán, Argentina.
| | - Fernando Gomollón
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Instituto de Investigaciones Sanitarias de Aragón, Hospital Clínico Universitario Lozano Blesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestiva (CIBEREHD), Zaragoza, España
| | - Juan Andrés De Paula
- Servicio de Gastroenterología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
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Busto-Iglesias M, Rodríguez-Martínez L, Rodríguez-Fernández CA, González-López J, González-Barcia M, de Domingo B, Rodríguez-Rodríguez L, Fernández-Ferreiro A, Mondelo-García C. Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review. Pharmaceutics 2023; 15:pharmaceutics15030766. [PMID: 36986627 PMCID: PMC10051556 DOI: 10.3390/pharmaceutics15030766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians’ treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.
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Affiliation(s)
- Manuel Busto-Iglesias
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain (C.M.-G.)
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
| | - Lorena Rodríguez-Martínez
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
| | - Carmen Antía Rodríguez-Fernández
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
- Ophthalmology Department, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Jaime González-López
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain (C.M.-G.)
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
| | - Miguel González-Barcia
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain (C.M.-G.)
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
| | - Begoña de Domingo
- Ophthalmology Department, University Clinical Hospital of Santiago Compostela (SERGAS), 15706 Santiago de Compostela, Spain
| | - Luis Rodríguez-Rodríguez
- Musculoskeletal Pathology Group, Hospital Clínico San Carlos, Instituto Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
- Correspondence: (L.R.-R.); (A.F.-F.)
| | - Anxo Fernández-Ferreiro
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain (C.M.-G.)
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
- Correspondence: (L.R.-R.); (A.F.-F.)
| | - Cristina Mondelo-García
- Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain (C.M.-G.)
- Pharmacology Group, Health Research Institute of Santiago de Compostela (FIDIS), 15706 Santiago de Compostela, Spain
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26
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Bjørlykke KH, Jahnsen J, Brynskov J, Molander P, Eberhardson M, Davidsdottir LG, Sipponen T, Hjortswang H, Goll GL, Syversen SW, Langholz E, Jørgensen KK, Steenholdt C. Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia. Scand J Gastroenterol 2023; 58:25-33. [PMID: 35996928 DOI: 10.1080/00365521.2022.2108684] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. METHODS A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. RESULTS In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. CONCLUSION TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.
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Affiliation(s)
- Kristin H Bjørlykke
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørn Brynskov
- Department of Gastroenterology, Herlev Hospital, Herlev, Denmark
| | - Pauliina Molander
- Abdominal Center, Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Michael Eberhardson
- Department of Gastroenterology, University Hospital, Linköping, Sweden and Karolinska Institutet, Stockholm, Sweden
| | - Loà G Davidsdottir
- Department of Gastroenterology, Landspítali, University Hospital of Iceland, Reykjavik, Iceland
| | - Taina Sipponen
- Abdominal Center, Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Henrik Hjortswang
- Department of Gastroenterology, University Hospital, Linköping, Sweden and Karolinska Institutet, Stockholm, Sweden
| | - Guro Løvik Goll
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Silje Watterdal Syversen
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Ebbe Langholz
- Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Kristin K Jørgensen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
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27
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Sethi S, Dias S, Kumar A, Blackwell J, Brookes MJ, Segal JP. Meta-analysis: The efficacy of therapeutic drug monitoring of anti-TNF-therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2022; 57:1362-1374. [PMID: 36495020 DOI: 10.1111/apt.17313] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/21/2022] [Accepted: 11/07/2022] [Indexed: 04/20/2023]
Abstract
BACKGROUND AND AIMS This systematic review and meta-analysis aimed to determine whether the use of therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients on anti-tumour necrosis factor (anti-TNF) therapy results in improved rates of clinical and endoscopic remission, surgery, corticosteroid-free remission and hospitalisation. METHODS MEDLINE, EMBASE, EMBASE classic, PubMed, Cochrane central databases register of controlled trials and Cochrane Specialised Trials Register were searched between 01 Janurary 1946 and 08 April 2022. Randomised controlled trials (RCTs) and prospective and retrospective observational studies were included, comparing TDM to standard of care (SOC) or reactive vs proactive TDM. Results were reported as pooled relative risks (RR) with 95% confidence intervals (95% CI). RESULTS Twenty-six studies, including 9 RCTs, were included. Compared to SOC, proactive TDM was associated with a significantly decreased risk of treatment failure (RR 0.64, 95% CI 0.48-0.85 p<0.01), and a non-significant decrease in need for surgery (RR 0.51, 95% CI 0.25-1.02) and hospitalisation (RR 0.64, 95% CI 0.40-1.00). Furthermore compared to SOC, Proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI 0.93-1.53) and clinical remission (RR 1.07, 95% CI 0.97-1.18). Compared to reactive TDM, proactive TDM was associated with significant decreased risk of treatment failure (RR 0.46, 95% CI 0.21 = 0.98, p = 0.04) and significant reduction in hospitalisation (RR 0.33, 95% CI 0.21-0.54, p < 0.01). CONCLUSIONS Compared to SOC, proactive TDM was associated with significant benefit in reducing treatment failure. Compared to reactive TDM, proactive TDM led to a significant reduction in hospitalisation and treatment failure. More studies with larger RCTs and standardised assays are needed to substantiate these results and validate the cost-effectiveness of TDM.
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Affiliation(s)
- Sonika Sethi
- Department of Gastroenterology, Sandwell and West Birmingham NHS Trust, West Midlands, West Bromwich, UK
| | - Shiluka Dias
- Department of Gastroenterology, Guys and St Thomas' NHS Trust, London, UK
| | - Aditi Kumar
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Jonathan Blackwell
- Department of Gastroenterology, Croydon Healthcare NHS Trust, London, UK
| | - Matthew J Brookes
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
- Research Institute in Healthcare Sciences, University of Wolverhampton, Wolverhampton, UK
| | - Jonathan P Segal
- Department of Medicine, University of Melbourne, Melbourne, Australia
- Department of Gastroenterology, Northern Hospital, Epping, Melbourne, Australia
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28
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Fernandes SR, Rodrigues IC, Serrazina J, Botto IA, Bernardo S, Gonçalves AR, Valente A, Moura Santos P, Correia LA, Marinho RT. Proactive infliximab is more effective than vedolizumab in inducing fecal calprotectin remission in inflammatory bowel disease. Scand J Gastroenterol 2022; 57:1202-1208. [PMID: 35599574 DOI: 10.1080/00365521.2022.2076567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Current evidence suggests vedolizumab (VDZ) may be as effective as Infliximab (IFX) in inflammatory bowel disease. It is unknown if proactive therapeutic drug monitoring (PTDM) of IFX may improve these results. METHODS Case-control study including consecutive patients with primary response to conventional IFX (n = 70), proactive IFX (n = 148), and VDZ (n = 95). PTDM was performed at week 14 and every other infusion, aiming at a trough level between 5 and 10 µg/ml. The primary outcome was fecal calprotectin (Fc) remission (<250 µg/g) at 1 year of treatment. Secondary outcomes included Fc remission at week 14 (proactive IFX/VDZ), clinical remission, treatment discontinuation, hospitalization, and surgery at 1-year of follow-up. RESULTS Proactive IFX was superior to conventional IFX and VDZ in inducing Fc remission at 1-year (69.4% vs 47.1% vs 37.9%, p = .003 and p < .001). Results remained significant in biologic naïve patients (70.8% vs 44.4% vs 51.4%, p = .001 and p = .043) but comparisons between conventional IFX and VDZ were not significant (p = .265 and p = .664). In multivariate analysis correcting for prior biologic exposure, proactive IFX was more effective than conventional IFX (OR 2.480 95%CI [1.367-4.499], p = .003) and VDZ (OR 3.467 95%CI [1.578-7.617], p = .002) in inducing Fc remission. Amongst secondary outcomes, only clinical remission was significant between proactive IFX and VDZ in the overall cohort (80.4% vs 55.8%, p < .001) and in biologic naïve patients (80.2% vs 62.9%, p = .043). Fc remission at 1-year was associated with better results in most secondary outcomes. CONCLUSION Proactive IFX was superior to VDZ in inducing Fc remission at 1-year, which was associated with improved clinical outcomes.SUMMARYCurrent evidence suggests that vedolizumab may be as effective as Infliximab in the treatment of patients with inflammatory bowel disease.There have been no studies comparing vedolizumab with proactively optimized Infliximab based on trough levels.We confirm that conventional IFX is as effective as vedolizumab but proactive IFX appears superior to vedolizumab in inducing fecal calprotectin remission.Fecal calprotectin remission associates with better clinical outcomes.
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Affiliation(s)
- Samuel Raimundo Fernandes
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Inês Coelho Rodrigues
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Juliana Serrazina
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Inês Ayala Botto
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Sónia Bernardo
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Ana Rita Gonçalves
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Ana Valente
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Paula Moura Santos
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Luís Araújo Correia
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
| | - Rui Tato Marinho
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
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29
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Vaughan R, Murphy E, Nalder M, Gibson RN, Ardalan Z, Boussioutas A, Christensen B. Infliximab Trough Levels Are Associated With Transmural Sonographic Healing in Inflammatory Bowel Disease. Inflamm Bowel Dis 2022:6696163. [PMID: 36094156 DOI: 10.1093/ibd/izac186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Mucosal healing improves clinical outcomes in patients with inflammatory bowel disease (IBD) and is associated with higher infliximab trough levels (ITLs). Transmural healing, assessed by intestinal ultrasound (IUS), is emerging as an objective target in Crohn's disease (CD) and ulcerative colitis (UC). This study explores the correlation between maintenance ITLs and sonographic transmural healing. METHODS Patients on maintenance infliximab therapy were prospectively enrolled to undergo paired IUS examination and serum ITL. Infliximab trough levels were compared between patients with and without sonographic markers of inflammation using the Mann-Whitney U test. RESULTS A prospective cohort of 103 patients (51% male; 79 CD; 24 UC; median duration of disease 8 years) underwent IUS and serum ITL testing. Forty-one percent of CD and 66% of UC patients demonstrated sonographic healing (bowel wall thickening ≤3 mm with no increase in color Doppler signal). Crohn's disease patients with sonographic healing had higher median ITL compared with those with sonographic inflammation (4.8 μg/mL vs 3.1 μg/mL; P = .049). Additionally, the presence of hyperemia on Doppler was independently associated with lower ITL compared with those without hyperemia (2.1 μg/mL vs 4.2 μg/mL, respectively; P = .003). There was no significant association between ITL and other sonographic markers of inflammation. In UC, lower ITL was associated with hyperemia on Doppler imaging (P = .04). There was no association between ITL and sonographic healing or any other individual sonographic parameter of inflammation. CONCLUSIONS Lower maintenance infliximab levels are associated with sonographic parameters of inflammation in UC and CD. Further studies are needed to determine whether targeting higher infliximab levels can increase sonographic healing.
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Affiliation(s)
- Rose Vaughan
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Elise Murphy
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia.,Pharmacy, The Royal Melbourne Hospital, Melbourne, Australia
| | - Michelle Nalder
- Pharmacy, The Royal Melbourne Hospital, Melbourne, Australia
| | - Robert N Gibson
- Department of Radiology, The Royal Melbourne Hospital and The University of Melbourne, Melbourne, Australia
| | - Zaid Ardalan
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia
| | - Alex Boussioutas
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Britt Christensen
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
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30
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Petric Z, Goncalves J, Paixao P. Under the Umbrella of Clinical Pharmacology: Inflammatory Bowel Disease, Infliximab and Adalimumab, and a Bridge to an Era of Biosimilars. Pharmaceutics 2022; 14:1766. [PMID: 36145514 PMCID: PMC9505802 DOI: 10.3390/pharmaceutics14091766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Monoclonal antibodies (MAbs) have revolutionized the treatment of many chronic inflammatory diseases, including inflammatory bowel disease (IBD). IBD is a term that comprises two quite similar, yet distinctive, disorders-Crohn's disease (CD) and ulcerative colitis (UC). Two blockbuster MAbs, infliximab (IFX) and adalimumab (ADL), transformed the pharmacological approach of treating CD and UC. However, due to the complex interplay of pharmacology and immunology, MAbs face challenges related to their immunogenicity, effectiveness, and safety. To ease the burden of IBD and other severe diseases, biosimilars have emerged as a cost-effective alternative to an originator product. According to the current knowledge, biosimilars of IFX and ADL in IBD patients are shown to be as safe and effective as their originators. The future of biosimilars, in general, is promising due to the potential of making the health care system more sustainable. However, their use is accompanied by misconceptions regarding their effectiveness and safety, as well as by controversy regarding their interchangeability. Hence, until a scientific consensus is achieved, scientific data on the long-term effectiveness and safety of biosimilars are needed.
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Affiliation(s)
- Zvonimir Petric
- Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
| | - Joao Goncalves
- Biopharmaceutical and Molecular Biotechnology Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
| | - Paulo Paixao
- Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
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31
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Lepus CA, Hyams JS. Barriers From Third-Party Payers to Biologic Use in Pediatric Inflammatory Bowel Disease. JPGN REPORTS 2022; 3:e215. [PMID: 37168642 PMCID: PMC10158370 DOI: 10.1097/pg9.0000000000000215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/04/2022] [Indexed: 05/13/2023]
Abstract
Biologic agents are now standard of care in the treatment of inflammatory bowel disease (IBD). The ability to use biologics in clinical practice is in part dictated by insurance company policies. There is a long delay between adult and pediatric approval of biologic agents, and these therapies are often denied by third-party payers for use in pediatric IBD patients. This study prospectively identified pediatric patients with IBD who were started on a biologic medication at our institution, and third-party payer decisions were recorded. There were no denials in patients with Medicaid, but private payers frequently interfered with use of biologic agents. Reasons for denial are generally for use of a specific off-label agent or dosing of an approved agent. These denials lead to delayed treatment, nonmedically sound changes in therapy, and increased administrative burden on providers.
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Affiliation(s)
- Chelsea A. Lepus
- From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, CT
| | - Jeffrey S. Hyams
- From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, CT
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32
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Lodhia N, Rao S. Updates in therapeutic drug monitoring in inflammatory bowel disease. World J Gastroenterol 2022; 28:2282-2290. [PMID: 35800180 PMCID: PMC9185221 DOI: 10.3748/wjg.v28.i21.2282] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/09/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
Biologics and immunomodulators (IMM) are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn's disease. However, despite the efficacy of these therapies, many patients either have a primary lack of response or a secondary loss of response to these medications. Therapeutic drug monitoring (TDM) is a systematic approach to managing such patients. In this review, we summarize the latest data on TDM, including reactive and proactive TDM, in patients with inflammatory bowel disease on biologics and/or IMM.
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Affiliation(s)
- Nilesh Lodhia
- Department of Gastroenterology and Hepatology, Atrium Health, Charlotte, NC 28203, United States
| | - Shanti Rao
- Department of Gastroenterology and Hepatology, Atrium Health, Charlotte, NC 28203, United States
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33
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Wang MY, Zhao JW, Zheng CQ, Sang LX. Therapeutic drug monitoring in inflammatory bowel disease treatments. World J Gastroenterol 2022; 28:1604-1607. [PMID: 35582129 PMCID: PMC9048458 DOI: 10.3748/wjg.v28.i15.1604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/06/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Recently, biological drugs have played a leading role in the treatment of inflammatory bowel disease, and therapeutic drug monitoring (TDM) may be useful in maximizing their effectiveness. TDM involves the measurement of serum drug and anti-drug antibodies concentrations as the basis for dosage adjustments or drug conversions to achieve a higher response rate. We believe that concentration thresholds should be individualized based on patients’ disease severity, extent and phenotype, and therapeutic purposes should also be considered, with higher cut-offs mainly needed for endoscopic and fistula healing than for symptomatic remission. Proactive and reactive TDM can help optimize treatment, especially in patients receiving anti-tumour necrosis factor, and guide dose adjustment or drug conversion with lower cost. TDM is a promising approach to achieve precision medicine and targeted medicine in the future.
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Affiliation(s)
- Meng-Yao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Jing-Wen Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Chang-Qing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
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34
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Cogan RC, El-Matary BW, El-Matary WM. Therapeutic drug monitoring for biological medications in inflammatory bowel disease. Saudi J Gastroenterol 2022; 28:322-331. [PMID: 35343213 PMCID: PMC9752529 DOI: 10.4103/sjg.sjg_3_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Therapeutic drug monitoring (TDM) is the measurement of serum drug concentrations and anti-drug-antibodies (ADA) for biologic therapies used to treat inflammatory bowel disease (IBD). The aim of this article is to review the current literature concerning reactive and proactive TDM for both adults and children with IBD. Although optimal trough concentration windows for some of these medications are not well defined, there is mounting evidence to suggest that reactive TDM is associated with favorable therapeutic outcomes, including less immunogenicity, greater drug exposure, and a decreased risk of treatment failure. Moreover, while the exact mechanism of loss of response is not fully elucidated, the vast majority of studies have reported a decreased incidence of nonresponse and secondary loss of response when TDM is implemented. Proactive TDM, while even less understood in the literature, employs a schedule of preemptive analysis of serum trough concentrations to accordingly adjust the patient's biologic dosage. Proactive TDM may decrease the need for IBD-related surgery/hospitalization, and therefore merits future studies of investigation.
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Affiliation(s)
- Rachel C. Cogan
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Basem W. El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Wael M. El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada,Address for correspondence: Dr. Wael M. El-Matary, Professor of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, AE 408 Children's Hospital, Health Sciences Centre, 840 Sherbrook St., Winnipeg, Manitoba, R3A 1S1, Canada. E-mail:
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35
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Shmais M, Regueiro M, Hashash JG. Proactive versus Reactive Therapeutic Drug Monitoring: Why, When, and How? Inflamm Intest Dis 2022; 7:50-58. [PMID: 35224018 PMCID: PMC8820143 DOI: 10.1159/000518755] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/12/2021] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Up to a third of inflammatory bowel disease) patients show primary nonresponse to antitumor necrosis factor (anti-TNF) biological therapy, and of those who respond, up to 40% develop secondary loss of response (LOR). Therapeutic drug monitoring (TDM) plays a crucial role in assessing patients with LOR to guide therapy by giving more of the drug or switching to a different biological agent. Although reactive TDM is suggested or recommended by the majority of gastroenterology associations, proactive TDM seems to be more controversial. SUMMARY In this article, we discuss the updated guidelines on TDM and will also discuss the available data supporting proactive and reactive TDM in patients with Crohn's disease and those with ulcerative colitis using the different available biological agents. KEY MESSAGES Therapeutic drug monitoring (TDM) is a valuable tool to aid in inflammatory bowel disease (IBD) therapy optimization. Reactive TDM is widely accepted in IBD patients with suspected loss of response, especially in those receiving antitumor necrosis factor (anti-TNF) agents. Proactive TDM is emerging as a reasonable approach to patients initiated on anti-TNF therapy, specifically infliximab and, to some extent, adalimumab, particularly for patients with severe ulcerative colitis and fistulizing Crohn's disease. Similarly, TDM may play a role in patients considering de-escalation from combination therapy. To date, proactive TDM is not widely applied to ustekinumab and vedolizumab and more data are required before this becomes part of clinical practice.
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Affiliation(s)
- Manar Shmais
- Division of Gastroenterology and Hepatology, American University of Beirut, Beirut, Lebanon
| | - Miguel Regueiro
- Division of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Jana G. Hashash
- Division of Gastroenterology and Hepatology, American University of Beirut, Beirut, Lebanon
- Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Mayo Clinic, Jacksonville, Florida, USA
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36
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Munir A, Hu L. Synthesized Drug from Medicinal Plant phytochemicals Effectively Targets ECM1 Gene Mutations in Ulcerative Colitis. LETT DRUG DES DISCOV 2022. [DOI: 10.2174/1570180818666210804130050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
:
Ulcerative colitis (UC); an inflammatory bowel disease primarily affects the mucosa of
the colon. Depending on its mode of appearance, it can affect either the entire colon or even the distal
rectum. UC can manifest in both genders and every generation, but most generally appear in people
between the ages of 15 and 30. The extracellular matrix protein-1 (ECM1) gene is an important
candidate, mutations leading to tissue damage in patients with ECM1 single-nucleotide polymorphisms
are likely to intensify tissue damage caused by Metalloproteinase9 resulting in UC. In this
analysis, approval for the synthesis of Chemical Compound was obtained from the scientific committee
of the Department of Traditional Chinese Medicine, Qilu Hospital, China. Several derivatives
used as UC therapy were selected to build the pharmacophore model, using a ligand-based pharmacophore
modeling approach and virtual screenings were done for the identification of suitable drug
compounds. The selected compound was then synthesized in-vitro and validated using the molecular
docking technique. The synthesized compound fulfills all the characteristics of the non-toxic existence
of other drug-likeness laws. The specific interactive amino acids found in the docked complex
are arginine (ARG):47, lysine (LYS):54, phenylalanine (PHE):141, aspargine (ASN):51, serine
(SER):219, histadine (HIS):144, PHE:214, valine(VAL):220, tyrosine(TYR):145, and TYR:284. The
interaction of the synthesized compound with mutated TYR:284 of ECM1 confirmed the viability
and safety of a drug molecule as a medication in Ulcerative Colitis care. In the future, its validity can
be explored in the laboratory and this synthesized compound can be used as a medication target in
clinical studies against TYR:284 mutation in the ECM1 gene.
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Affiliation(s)
- Anum Munir
- Department of Biotechnology, Comsats University Islamabad, Abbottabad Campus, 22010, Abbottabad, Pakistan
| | - Lianhai Hu
- Department of Traditional Chinese Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No.
107 Wenhuaxi Road, Jinan, Shandong Province, 250012, China
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37
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Syversen SW, Jørgensen KK, Goll GL, Brun MK, Sandanger Ø, Bjørlykke KH, Sexton J, Olsen IC, Gehin JE, Warren DJ, Klaasen RA, Noraberg G, Bruun TJ, Dotterud CK, Ljoså MKA, Haugen AJ, Njålla RJ, Zettel C, Ystrøm CM, Bragnes YH, Skorpe S, Thune T, Seeberg KA, Michelsen B, Blomgren IM, Strand EK, Mielnik P, Torp R, Mørk C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA 2021; 326:2375-2384. [PMID: 34932077 PMCID: PMC8693274 DOI: 10.1001/jama.2021.21316] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. OBJECTIVE To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. DESIGN, SETTING, AND PARTICIPANTS Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. INTERVENTIONS Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). MAIN OUTCOME AND MEASURES The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. RESULTS Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03074656.
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Affiliation(s)
| | | | - Guro Løvik Goll
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Marthe Kirkesæther Brun
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Kristin Hammersbøen Bjørlykke
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Joseph Sexton
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Inge Christoffer Olsen
- Department of Research Support for Clinical Trials, Oslo University Hospital, Oslo, Norway
| | - Johanna Elin Gehin
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - David John Warren
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Rolf Anton Klaasen
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Geir Noraberg
- Department of Gastroenterology, Hospital of Southern Norway Trust, Arendal, Norway
| | - Trude Jannecke Bruun
- Department of Rheumatology, The University Hospital of North Norway, Tromsø, Norway
| | | | | | | | | | - Camilla Zettel
- Department of Rheumatology, Betanien Hospital, Skien, Norway
| | | | | | - Svanaug Skorpe
- Haugesund Hospital for Rheumatic Diseases, Haugesund, Norway
| | - Turid Thune
- Department of Dermatology, Haukeland University Hospital, Bergen, Norway
| | | | - Brigitte Michelsen
- Division of Rheumatology, Department of Medicine, Hospital of Southern Norway Trust, Kristiansand, Norway
| | | | | | - Pawel Mielnik
- Department of Neurology, Rheumatology, and Physical Medicine, Førde Hospital Trust, Førde, Norway
| | - Roald Torp
- Department of Medicine, Innlandet Hospital Trust, Hamar, Norway
| | - Cato Mørk
- Akershus Dermatology Center, Lørenskog, Norway
| | - Tore K. Kvien
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Espen A. Haavardsholm
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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Fernandes SR, Serrazina J, Rodrigues IC, Bernardo S, Rita Gonçalves A, Valente A, Baldaia C, Santos PM, Correia LA, Tato Marinho R. Proactive therapeutic drug monitoring is more effective than conventional management in inducing fecal calprotectin remission in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2021; 33:1539-1546. [PMID: 33731596 DOI: 10.1097/meg.0000000000002111] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Proactive therapeutic drug monitoring (pTDM) may improve treatment outcomes in inflammatory bowel disease. AIMS AND METHODS We compared 135 patients following a prospective pTDM protocol aiming at an infliximab trough level (IFXTL) between 5 and 10 μg/ml with sequential measurements of Fc, with 108 patients from a retrospective group under conventional management. We evaluated the rates of Fc remission (<250 μg/g) and other clinical outcomes at 2-year of follow-up. RESULTS pTDM associated with higher rates of Fc remission (69.6% vs. 50.0%; P = 0.002), and steroid-free clinical remission (78.4% vs. 55.2%, P = 0.028) with a trend for clinical remission (79.3% vs. 68.5%, P = 0.075). There was no difference in treatment discontinuation (P = 0.195), hospitalization (P = 0.156), and surgery (P = 0.110). Higher IFXTL associated with Fc remission at week 14 (6.59 vs. 2.96 μg/ml, P < 0.001), and at the end of follow-up (8.10 vs. 5.03 μg/ml, P = 0.001). In patients reaching Fc remission after week 14, IFXTL increased from week 14 to the end of follow-up (2.71 vs. 8.54 μg/ml, P < 0.001). Fc remission associated with higher rates of clinical (85.8% vs. 56.8% P < 0.001) and steroid-free clinical remission (86.9% vs. 50.0% P < 0.001), lower IFX discontinuation (8.8% vs. 36.8%, P < 0.001), and hospitalization (13.5% vs. 33.7%, P < 0.001), without significance for surgery (6.1% vs. 12.6%, P = 0.101). CONCLUSION pTDM was more effective than conventional management in inducing Fc remission which was associated with improved outcomes.
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Affiliation(s)
- Samuel Raimundo Fernandes
- Department of Gastrenterology and Hepatology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
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Ustekinumab induction concentrations are associated with clinical and biochemical outcomes at week 12 of treatment in Crohn's disease. Eur J Gastroenterol Hepatol 2021; 33:e401-e406. [PMID: 33731595 DOI: 10.1097/meg.0000000000002116] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND We investigated relationships between induction ustekinumab levels and clinical and biochemical outcomes in Crohn's disease. METHODS Following standard IV induction, ustekinumab levels were measured at week 2 (wk2) and week 6 (wk6). Ustekinumab levels were compared in patients receiving 260, 390 and 520 mg at induction. Crohn's disease activity index (CDAI), serum albumin, C-reactive protein (CRP) and fecal calprotectin (FCP) were measured at baseline and week 12 (wk12). Associations between ustekinumab levels and these parameters were assessed. Ustekinumab levels were compared between patients requiring dose intensification within one year of induction and those remaining on standard dosing. RESULTS Of 23 wk2 ustekinumab levels, 22(95.7%) were above the upper limit of quantification of the assay (25 µg/mL). Median wk6 ustekinumab level (n = 25) was 14.2 μg/mL [interquartile range (IQR), 9.6-20.1]. Median wk6 ustekinumab levels in patients receiving 260, 390 and 520 mg were 8.6, 16.3 and 25.0 µg/mL, respectively, P = 0.01. There were significant correlations between baseline albumin and wk6 ustekinumab levels; r = 0.644 [95% confidence interval (CI), 0.304-0.839], P < 0.001, and between baseline FCP and wk6 ustekinumab levels; r = -0.678 (95% CI, -0.873 to -0.296), P < 00.01. Median wk12 CDAI (n = 18), CRP (n = 22) and FCP (n = 13) were 78 (IQR, 52.5-152), 1.75 mg/L (IQR, 0.93-7.03) and 746 μg/g (IQR, 259-2100), respectively. There were significant correlations between wk6 ustekinumab levels and wk12 CDAI; r = -0.513 (95% CI, -0.796 to -0.046), P = 0.03; and between wk6 ustekinumab levels and wk12 CRP; r = -0.578 (95% CI, -0.808 to -0.194), P < 0.01. Wk6 ustekinumab levels were lower in patients undergoing subsequent dose intensification; 12.5 vs. 19.6 µg/mL, P = 0.04. CONCLUSION Wk6 ustekinumab levels are significantly associated with baseline Crohn's disease biomarkers and subsequent clinical and biochemical outcomes.
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Sorrentino D, Nguyen VQ, Love K. Fecal Lactoferrin Predicts Primary Nonresponse to Biologic Agents in Inflammatory Bowel Disease. Dig Dis 2021; 39:626-633. [PMID: 33631768 PMCID: PMC8686729 DOI: 10.1159/000515432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. METHODS Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3-24 months). RESULTS Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). CONCLUSIONS In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.
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Affiliation(s)
- Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA,Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, Udine, Italy,*Dario Sorrentino,
| | - Vu Q. Nguyen
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
| | - Kim Love
- K.R. Love Quantitative Consulting and Collaboration, Athens, Georgia, USA
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Salvador-Martín S, Melgarejo-Ortuño A, López-Fernández LA. Biomarkers for Optimization and Personalization of Anti-TNFs in Pediatric Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13111786. [PMID: 34834201 PMCID: PMC8617733 DOI: 10.3390/pharmaceutics13111786] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/11/2021] [Accepted: 10/15/2021] [Indexed: 12/14/2022] Open
Abstract
The use of biological drugs has improved outcomes in pediatric inflammatory bowel disease (IBD). Prediction of the response to biological drugs would be extremely useful in IBD, and even more so in children, who are still growing physically and psychologically. Specific clinical, biochemical, and genetic parameters are considered predictive of response to biological drugs, although few studies have been carried out in children with IBD. In this review, we present current evidence on biological treatments used in pediatric IBD and the available biomarkers of response. We examine demographics, clinical characteristics, biomarkers (genetic, genomic, and cellular), and microbiota.
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Affiliation(s)
- Sara Salvador-Martín
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
| | - Alejandra Melgarejo-Ortuño
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
| | - Luis A. López-Fernández
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
- Spanish Clinical Research Network (SCReN), 28040 Madrid, Spain
- Correspondence:
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Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27:6231-6247. [PMID: 34712029 PMCID: PMC8515794 DOI: 10.3748/wjg.v27.i37.6231] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/08/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
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Affiliation(s)
- Farah Albader
- Department of Internal Medicine, McGill University, Montreal H3G1A4, Quebec, Canada
| | - Petra Anna Golovics
- Division of Gastroenterology, Hungarian Defence Forces, Medical Centre, Budapest H-1062, Hungary
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, Budapest H-1083, Hungary
| | - Talat Bessissow
- Division of Gastroenterology, McGill University Health Centre, Montreal H3G 1A4, Quebec, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
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Hashash JG, Fadel CGA, Rimmani HH, Sharara AI. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn's disease and ulcerative colitis. Ann Gastroenterol 2021; 34:612-624. [PMID: 34475731 PMCID: PMC8375659 DOI: 10.20524/aog.2021.0645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/12/2021] [Indexed: 12/19/2022] Open
Abstract
Despite current guidelines, the optimal treatment of patients with inflammatory bowel disease (IBD) remains challenging. The available medications are not without risk and there is not a single correct treatment regimen for every patient. Personalizing treatment and selecting the most appropriate therapy is crucial for optimal response, remission, quality of life, and healthcare utilization. Biologics, especially anti-tumor necrosis factor-α medications, are widely used in the induction and maintenance of disease remission in patients with IBD. Similarly, immunomodulators, including thiopurines and methotrexate, are traditionally popular for the maintenance of remission. In this manuscript, we review the use of biologic monotherapy vs. combination therapy with immunomodulators for the treatment of ulcerative colitis and Crohn’s disease. We examine overall remission, immunogenicity and adverse effects, mainly serious infections and malignancy, in an effort to help guide treatment decisions and weigh the risks and benefits of biologic monotherapy vs. combination therapy.
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Affiliation(s)
- Jana G Hashash
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Carla G Abou Fadel
- Division of Gastroenterology, Bellevue Medical Center, Mansourieh (Carla G. Abou Fadel), Lebanon
| | - Hussein H Rimmani
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Ala I Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
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Blesl A, Binder L, Högenauer C, Wenzl H, Borenich A, Pregartner G, Berghold A, Mestel S, Kump P, Baumann‐Durchschein F, Petritsch W. Limited long-term treatment persistence of first anti-TNF therapy in 538 patients with inflammatory bowel diseases: a 20-year real-world study. Aliment Pharmacol Ther 2021; 54:667-677. [PMID: 34151449 PMCID: PMC8453765 DOI: 10.1111/apt.16478] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/12/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Anti-TNF antibodies were the first biologic treatment option for patients with inflammatory bowel diseases. AIMS To assess length of treatment persistence of first anti-TNF therapy and influencing factors used in the standard care of patients with inflammatory bowel diseases. METHODS Single-centre, retrospective study from a register including patients who received anti-TNF therapy in the last 20 years at the study centre. Kaplan-Meier analysis with log-rank test was used to describe treatment persistence. With multivariable Cox regression analysis, risk factors for treatment failure were investigated. RESULTS Five hundred thirty-eight patients (CD, Crohn's disease: 367, UC, ulcerative colitis: 147, inflammatory bowel disease unclassified: 24) with a median follow-up of 8.1 years were included. Median (95% confidence interval) treatment persistence in the total cohort was 2.3 years (28 [22, 38] months), and nearly half of patients withdrew from treatment within 2 years. Male patients were treated longer than females (male: 37 [25, 48] months, female: 23 [14, 33] months, P = 0.002). Treatment persistence was longer in CD compared to UC (CD: 39 [30, 50] months, UC: 13 [9, 19] months, P < 0.001), and patients with CD remained longer on adalimumab than on infliximab treatment (adalimumab: 67 [55, 95] months, infliximab: 19 [14, 31] months, P < 0.001). Treatment failure (52%) and side effects (25%) were the most common reasons for withdrawal from therapy; 14% withdrew due to remission. Female sex was identified as independent predictor for treatment failure in UC (hazard ratio [CI]: 1.73 [1.02-2.92], P = 0.04). CONCLUSION Long-term treatment persistence of first anti-TNF therapy was limited in patients with inflammatory bowel diseases, primarily due to treatment failure and side effects.
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Affiliation(s)
- Andreas Blesl
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Lukas Binder
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Christoph Högenauer
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria,BiotechmedGrazAustria
| | - Heimo Wenzl
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Andrea Borenich
- Institute for Medical Informatics, Statistics and DocumentationMedical University of GrazGrazAustria
| | - Gudrun Pregartner
- Institute for Medical Informatics, Statistics and DocumentationMedical University of GrazGrazAustria
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics and DocumentationMedical University of GrazGrazAustria
| | - Sigrid Mestel
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Patrizia Kump
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | | | - Wolfgang Petritsch
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
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Blesl A, Högenauer C, Borenich A, Berghold A, Wenzl H, Petritsch W. Editorial: does anti-TNF 'treatment persistence' always equate to 'effective treatment'? Only objective disease assessments can answer the question. Authors' reply. Aliment Pharmacol Ther 2021; 54:720-721. [PMID: 34379834 DOI: 10.1111/apt.16535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Andreas Blesl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Christoph Högenauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.,Biotechmed, Graz, Austria
| | - Andrea Borenich
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Heimo Wenzl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Wolfgang Petritsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Grasmeier MK, Langmann AF, Langmann P, Treiber M, Thaler MA, Luppa PB. Dynamics of serum concentrations of antibodies to infliximab: a new approach for predicting secondary loss of response in inflammatory bowel diseases. Therap Adv Gastroenterol 2021; 14:17562848211037849. [PMID: 34434255 PMCID: PMC8381421 DOI: 10.1177/17562848211037849] [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: 04/28/2021] [Accepted: 07/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Antibodies to infliximab (ATI) in serum are associated with secondary loss of response (LOR) to infliximab (IFX) therapy in patients with inflammatory bowel disease (IBD). However, feasible ATI-related predictors of therapy success are lacking and knowledge about individual ATI dynamics is limited. Therefore, this study analyzed whether ATI dynamics are able to predict LOR to IFX therapy and compared their predictive power with known predictors of LOR to IFX. METHODS This was a retrospective study of patients with Crohn's disease (CD) or ulcerative colitis (UC) on IFX maintenance therapy and proactive IFX and immunogenicity monitoring in an outpatient clinic in Germany. Slopes of ATI (S ATI) and IFX levels (dynamic parameters) and medians of ATI, IFX, C-reactive protein, and fecal calprotectin (static parameters) were calculated over a defined period of time after ATI emergence. Dynamic and static parameters were analyzed for associations with end points infliximab discontinuation due to secondary LOR and total IFX discontinuation. RESULTS In all, 500 visits from 38 IBD patients (28 CD, 10 UC) with a median IFX maintenance duration of 68.2 weeks were evaluated. Grouping by S ATI (ATI-N = ATI nondetectable, ATI- ↓ = negative S ATI, ATI- ↑ = positive S ATI) yielded significant differences for outcomes LOR (p = 0.004) and total IFX discontinuation (p = 0.01). Patients in the ATI-↓ group survived significantly longer LOR-free compared with the ATI-↑ group (p = 0.02). Cox regression confirmed S ATI to be a significant risk factor for LOR (p = 0.002). An S ATI cut-off of approximately 2.0 AU mL-1 week-1 was determined to predict LOR with 83.3% sensitivity and 93.8% specificity. CONCLUSION The ATI slope-based index S ATI is a new feasible diagnostic predictor of LOR in IBD patients. S ATI may facilitate quick therapeutic decisions after ATI emerge.
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Affiliation(s)
- Melina K. Grasmeier
- Institut für Klinische Chemie und
Pathobiochemie, Klinikum rechts der Isar der Technischen Universität
München, München, Germany
| | - Anna F. Langmann
- Institut für Klinische Chemie und
Pathobiochemie, Klinikum rechts der Isar der Technischen Universität
München, München, Germany
| | - Peter Langmann
- Medizinische Fakultät,
Julius-Maximilians-Universität Würzburg, Würzburg, Germany;
Gastroenterologische Gemeinschaftspraxis, Prof. Dr. Peter Langmann and Dr.
Monika Weikert, Karlstadt, Germany
| | - Matthias Treiber
- Klinik und Poliklinik für Innere Medizin II,
Klinikum rechts der Isar der Technischen Universität München, München,
Germany
| | - Markus A. Thaler
- Institut für Klinische Chemie und
Pathobiochemie, Klinikum rechts der Isar der Technischen Universität
München, München, Germany
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47
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Hedin CRH, Sonkoly E, Eberhardson M, Ståhle M. Inflammatory bowel disease and psoriasis: modernizing the multidisciplinary approach. J Intern Med 2021; 290:257-278. [PMID: 33942408 DOI: 10.1111/joim.13282] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.
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Affiliation(s)
- C R H Hedin
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - E Sonkoly
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - M Eberhardson
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Gastroenterology, University Hospital in Linkoping, Linkoping, Sweden
| | - M Ståhle
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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48
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Mattoo VY, Basnayake C, Connell WR, Ding N, Kamm MA, Lust M, Niewiadomski O, Thompson A, Wright EK. Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease. Aliment Pharmacol Ther 2021; 54:249-266. [PMID: 34153124 DOI: 10.1111/apt.16479] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/12/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). AIMS To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. METHODS EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. RESULTS A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. CONCLUSIONS Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.
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Affiliation(s)
- Vandita Y Mattoo
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Chamara Basnayake
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - William R Connell
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Nik Ding
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Michael A Kamm
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Mark Lust
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Ola Niewiadomski
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Alexander Thompson
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Emily K Wright
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
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Bhattarai A, Kowalczyk W, Tran TN. A literature review on large intestinal hyperelastic constitutive modeling. Clin Biomech (Bristol, Avon) 2021; 88:105445. [PMID: 34416632 DOI: 10.1016/j.clinbiomech.2021.105445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/29/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023]
Abstract
Impacts, traumas and strokes are spontaneously life-threatening, but chronic symptoms strangle patient every day. Colorectal tissue mechanics in such chronic situations not only regulates the physio-psychological well-being of the patient, but also confirms the level of comfort and post-operative clinical outcomes. Numerous uniaxial and multiaxial tensile experiments on healthy and affected samples have evidenced significant differences in tissue mechanical behavior and strong colorectal anisotropy across each layer in thickness direction and along the length. Furthermore, this study reviewed various forms of passive constitutive models for the highly fibrous colorectal tissue ranging from the simplest linearly elastic and the conventional isotropic hyperelastic to the most sophisticated second harmonic generation image based anisotropic mathematical formulation. Under large deformation, the isotropic description of tissue mechanics is unequivocally ineffective which demands a microstructural based tissue definition. Therefore, the information collected in this review paper would present the current state-of-the-art in colorectal biomechanics and profoundly serve as updated computational resources to develop a sophisticated characterization of colorectal tissues.
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Affiliation(s)
- Aroj Bhattarai
- Department of Orthopaedic Surgery, University of Saarland, Germany
| | | | - Thanh Ngoc Tran
- Department of Orthopaedic Surgery, University of Saarland, Germany.
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50
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Chen BX, Han ZM, Zhou Q, Liu HB, Xu PC, Zhi FC. Efficacy of infliximab in treatment-naïve patients with stricturing small bowel Crohn's disease. Scand J Gastroenterol 2021; 56:812-819. [PMID: 33962533 DOI: 10.1080/00365521.2021.1922748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES The efficacy of infliximab in treatment-naïve patients with stricturing small bowel Crohn's disease (CD) has not been well studied. We aimed to evaluate the efficacy of infliximab in these patients. MATERIALS AND METHODS This was a retrospective study of all consecutive treatment-naïve patients with newly diagnosed CD with small bowel stricture who started regular infliximab therapy in Nanfang Hospital between January 2015 and December 2019. An effective infliximab therapy was defined as infliximab continuation without the use of steroids, new biologics, endoscopic interventions or intestinal surgery. RESULTS Seventy-nine patients were included. After a median 38 months follow-up, an effective infliximab therapy was achieved in 37 patients. Long diagnostic delay (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.78; p= .008), pre-stenotic dilatation (HR 0.17, 95%CI 0.09-0.35; p < .001), long segmental stricture (HR 0.20, 95%CI 0.10-0.41; p < .001), and penetrating disease (HR 0.22, 95%CI 0.10-0.49; p < .001) were negatively correlated with an effective infliximab therapy. CONCLUSIONS Infliximab is effective in nearly 50% of treatment-naïve patients with CD with small bowel stricture, and an effective therapy is more likely to be achieved in patients without long diagnostic delay, pre-stenotic dilatation, long segmental stricture or penetrating disease.
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Affiliation(s)
- Bing-Xia Chen
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Ze-Min Han
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Qian Zhou
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Hong-Bin Liu
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Pei-Chun Xu
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Fa-Chao Zhi
- Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
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