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Bortolin Fonseca C, Petry R, Harlacher L, Hanauer L, Magalhães Francesconi CF, Gustavo Kotze P, Flores C. Body mass index does not influence loss of response to tumor necrosis factor inhibitors in Crohn's disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502372. [PMID: 39914694 DOI: 10.1016/j.gastrohep.2025.502372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/25/2025]
Abstract
OBJECTIVES Moderate to severe Crohn's disease (CD) treatment was revolutionized by introducing anti-tumor necrosis factor (TNF) agents, which is still a cornerstone of the treatment. It is speculated that adipose tissue may influence treatment response, especially for non-weight-adjusted agents. PATIENTS AND METHODS Research comparing the effectiveness of anti-TNFs between eutrophic and overweight patients may impact clinical management. We performed a retrospective analysis of a CD patient database. The primary endpoint was loss of response (LOR) after 54 weeks with infliximab (IFX) and adalimumab (ADA) in patients with body mass index (BMI) <25 and ≥25. Secondary endpoints were steroid-free remission and endoscopic remission rate. RESULTS One hundred seventy-nine CD patients were evaluated; 48.9% had LOR after 54 weeks of anti-TNF therapy. Fifty-four patients had a BMI ≥25, with 51 receiving IFX and 28 receiving ADA. The univariate analysis identified LOR in 56.5% of the patients with IFX and 34.9% in the ADA group (p=0.009). In the 54-week multivariate analysis, loss of response in the IFX group with BMI ≥25 had a relative risk of 1.04 [CI 0.60-1.80 (p=0.891)] compared to patients with BMI <25. Being overweight or obese led to a risk of 1.50 for LOR for ADA at 54-week time point [CI 0.60-3.74 (p=0.0387)]. Clinical remission at 54 weeks was similar between BMI groups. CONCLUSIONS Being overweight did not influence the LOR to treatment when IFX and ADA were compared, nor did it affect clinical and endoscopic remission after 54 weeks.
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Affiliation(s)
| | - Roberta Petry
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Laryssa Hanauer
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Iovino NA, McClinchie MG, Abdel-Rasoul M, Boyle B, Dotson JL, Michel HK, Maltz RM. Clinical impacts of immunomodulator withdrawal from anti-tumor necrosis factor combination therapy in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 79:885-894. [PMID: 38946674 DOI: 10.1002/jpn3.12299] [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: 02/25/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/02/2024]
Abstract
OBJECTIVES Combination therapy consists of both anti-tumor necrosis factor (anti-TNF) and an immunomodulator (IMM) and has been shown to improve outcomes in patients with inflammatory bowel disease (IBD). This study assesses the impacts of IMM withdrawal from combination therapy to anti-TNF monotherapy in children with IBD. METHODS This single-center retrospective cohort study included children with IBD initiated on combination therapy between 2014 and 2019 who discontinued the IMM. We evaluated whether IMM withdrawal impacts laboratory values and disease activity. Linear mixed effects models with random intercepts were used to compare differences between groups. Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation of therapy. RESULTS One hundred and fifty-two patients discontinued the IMM which did not significantly affect disease activity. However, 18% of patients escalated therapy after IMM withdrawal, primarily due to low anti-TNF levels. Lower anti-TNF and higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before IMM withdrawal were associated with subsequent escalation of therapy. Overall, there was no statistically significant effect on anti-TNF drug levels. Patients with Crohn's disease (CD) on infliximab (IFX) and methotrexate (MTX) who discontinued the IMM had an increase in mean ESR and CRP (p < 0.05). CONCLUSIONS IMM withdrawal from anti-TNF combination therapy may be considered safe in the setting of higher anti-TNF levels and normal serum inflammatory markers. Clinicians should consider assessing anti-TNF levels and inflammatory markers after IMM withdrawal, especially in patients with CD receiving IFX who discontinued MTX.
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Affiliation(s)
| | - Madeline G McClinchie
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Mahmoud Abdel-Rasoul
- Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
- Biostatistics Resource, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Brendan Boyle
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jennifer L Dotson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- Center for Child Health Equity and Outcomes Research, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Hilary K Michel
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Ross M Maltz
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Gordon M, Sinopoulou V, Akobeng AK, Sarian A, Moran GW. Infliximab for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev 2024; 2:CD012609. [PMID: 38372447 PMCID: PMC10875719 DOI: 10.1002/14651858.cd012609.pub2] [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] [Indexed: 02/20/2024]
Abstract
BACKGROUND Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn's disease. OBJECTIVES To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn's disease. SEARCH METHODS On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP. SELECTION CRITERIA Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn's disease. DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events. MAIN RESULTS Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse. AUTHORS' CONCLUSIONS Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.
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Affiliation(s)
- Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | - Anthony K Akobeng
- Pediatric Gastroenterology, Sidra Medicine, Doha, Qatar
- Weill Cornell Medicine, Cornell University, Doha, Qatar
| | - Arni Sarian
- School of Medicine, University of Central Lancashire, Preston, UK
| | - Gordon William Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK
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Gorelik Y, Ghersin I, Shlon D, Friss C, Lujan R, Loewenberg Weisband Y, Greenfeld S, Kariv R, Ledderman N, Matz E, Dotan I, Bar-Yoseph H, Chowers Y, Turner D. Association of Antibiotic Use with Durability of Biologic Agents in Inflammatory Bowel Disease: a Report from the epi-IIRN. J Crohns Colitis 2023; 17:1410-1417. [PMID: 37084088 DOI: 10.1093/ecco-jcc/jjad070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Indexed: 04/22/2023]
Abstract
BACKGROUND Different antibiotic classes were reported to have variable effects on immunogenicity towards anti-tumour necrosis factor [TNF] agents. However, the impact of antibiotic administration on biologic treatment durability was not investigated. We aimed to assess the association between antibiotic treatment and persistence of different classes of biologic therapy in inflammatory bowel disease [IBD] patients. METHODS Data from the epi-IIRN, a nationwide registry of all Israeli IBD patients were analysed. All patients who filled a prescription of either infliximab, adalimumab, vedolizumab, or ustekinumab, were included. Treatment cessation was defined as drug discontinuation of at least 6 months. Macrolides, cephalosporins, fluoroquinolones, and penicillins with beta-lactamase inhibitors were selected as primary exposure variables. Survival analysis was performed using marginal structural models for each drug separately. RESULTS In all 13 513 IBD patients, with a total of 39 600 patient-years, were included. Significant differences of overall treatment persistence were demonstrated, with highest persistence rates for ustekinumab and the lowest for infliximab treatment. Macrolides were found to be significantly associated with reduced risk of infliximab cessation (adjusted hazard ratio [aHR] 0.72, 95% CI 0.62-0.89]. Fluoroquinolones and cephalosporins were associated with an elevated risk of adalimumab treatment cessation [aHR 1.33, 95% CI 1.22-1.46; and aHR 1.20, 95% CI 1.08-1.34, respectively]. No significant effects of the studied antibiotics were observed in ustekinumab and vedolizumab users. CONCLUSIONS Specific antibiotic classes are associated with duration of anti-TNF treatment, but not with durability of vedolizumab or ustekinumab treatments. Further research is required to study the effect of specific antibiotics on response to biologics.
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Affiliation(s)
- Yuri Gorelik
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Itai Ghersin
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Deema Shlon
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Chagit Friss
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | - Rona Lujan
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | | | - Shira Greenfeld
- Maccabi Health Services, Tel-Aviv, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Revital Kariv
- Maccabi Health Services, Tel-Aviv, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Natan Ledderman
- Meuhedet Health Services, Meuhedet Research Institue, Tel-Aviv, Israel
| | - Eran Matz
- Leumit Health Services, Leumit Research Institue, Tel-Aviv, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Yehuda Chowers
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
- Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
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Pretreating mesenchymal stem cells with IL-6 regulates the inflammatory response of DSS-induced ulcerative colitis in rats. Transpl Immunol 2023; 76:101765. [PMID: 36462558 DOI: 10.1016/j.trim.2022.101765] [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: 08/03/2022] [Revised: 08/30/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
The immunomodulatory properties of mesenchymal stem cells (MSCs) have been broadly investigated in research on inflammatory diseases including ulcerative colitis. Treating MSCs with an inflammatory stimulus before transplantation is an adaptive strategy that helps MSCs survive in areas of inflammation and promotes the regulation of local immune responses. This study aimed to examine the effects of pretreating bone marrow MSCs (BMSCs) with Interleukin-6 (IL-6) on attenuation of dextran sulfate sodium (DSS)-induced ulcerative colitis in rats. Experimental ulcerative colitis was induced in Wistar rats by administering 2% DSS in their water for 7 days and normal water for the next 3 days. The experimental group received 1 × 106/0.4 ml of BMSCs that were treated with IL-6 for 24 h. Histological changes, colon length, and disease activity index were compared among groups, and the levels of TNF-α, IL-6, and IL-1β in homogenate supernatants were evaluated using ELISA. IL-6-pretreated BMSCs significantly reduced the colonic damage score. The colon length shortened by 6.1 ± 0.14 cm for the rats that received IL-6-pretreated BMSCs, whereas the control group rats' value was 3.8 ± 0.14 cm on the 14th day. The levels of pro-inflammatory cytokines were significantly decreased in the colons of the IL-6-pretreated BMSCs group compared with those of the control group (p < 0.05). This study revealed that IL-6-pretreated BMSCs ameliorated DSS-induced colitis via local anti-inflammatory action and suggested that IL-6-pretreated BMSCs are a promising therapeutic agent for ulcerative colitis treatment.
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Rubín de Célix C, Chaparro M, Gisbert JP. Real-World Evidence of the Effectiveness and Safety of Ustekinumab for the Treatment of Crohn's Disease: Systematic Review and Meta-Analysis of Observational Studies. J Clin Med 2022; 11:4202. [PMID: 35887966 PMCID: PMC9317084 DOI: 10.3390/jcm11144202] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Evidence on the outcomes of ustekinumab treatment in real-world Crohn's disease (CD) patients is needed. Our aim was to evaluate the effectiveness and safety of ustekinumab in CD, reported by observational studies. (2) Methods: bibliographical searches were performed (PubMed, EMBASE). SELECTION observational studies assessing the effectiveness and safety of ustekinumab in CD. EXCLUSION CRITERIA studies using ustekinumab as a prophylaxis for postoperative recurrence or perianal disease. DATA SYNTHESIS effectiveness by intention-to-treat (random-effects model). Data were stratified by study design, population included, administered dose, and prior biologic exposure. (3) Results: A total of 63 studies (8529 patients) were included. Response was achieved in 60% (95% CI, 54-67%) in the short term (8-14 weeks); 64% (57-71%) in the medium term (16-24 weeks); and 64% (52-74%) in the long term (48-52 weeks). Remission was achieved in 37% (28-46%) in the short term; 42% (36-49%) in the medium term; and 45% (37-53%) in the long term. The endoscopic remission rate was 33% (25-40%) in the long term. Eighteen percent of patients lost response during follow-up. Nearly one-third of the patients needed dose optimisation, and in 59% of them it was effective. Twenty-five percent of patients developed adverse events, leading to treatment withdrawal in seven percent of the cases. (4) Conclusions: Ustekinumab is an effective and safe therapy in real-world refractory CD patients. Dose optimisation is frequently required, being effective in a high percentage of cases.
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Affiliation(s)
- Cristina Rubín de Célix
- Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain; (M.C.); (J.P.G.)
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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: 2] [Impact Index Per Article: 0.7] [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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8
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Qu JH, Ordutowski H, Van Tricht C, Verbruggen R, Barcenas Gallardo A, Bulcaen M, Ciwinska M, Gutierrez Cisneros C, Devriese C, Guluzade S, Janssens X, Kornblum S, Lu Y, Marolt N, Nanjappan C, Rutten E, Vanhauwaert E, Geukens N, Thomas D, Dal Dosso F, Safdar S, Spasic D, Lammertyn J. Point-of-care therapeutic drug monitoring of adalimumab by integrating a FO-SPR biosensor in a self-powered microfluidic cartridge. Biosens Bioelectron 2022; 206:114125. [DOI: 10.1016/j.bios.2022.114125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/31/2022] [Accepted: 02/20/2022] [Indexed: 12/11/2022]
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Ries M, Moulari B, Shetab Boushehri MA, Ali ME, Molnar D, Béduneau A, Pellequer Y, Lamprecht A. Adalimumab Decorated Nanoparticles Enhance Antibody Stability and Therapeutic Outcome in Epithelial Colitis Targeting. Pharmaceutics 2022; 14:pharmaceutics14020352. [PMID: 35214083 PMCID: PMC8879121 DOI: 10.3390/pharmaceutics14020352] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/28/2022] [Accepted: 01/30/2022] [Indexed: 02/01/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Although a deeper understanding of the underlying mechanisms of IBD has led to new therapeutic approaches, treatment options are still limited. Severe adverse events in conventional drug therapy and poor drug targeting are the main cause of early therapy failure. Nanoparticle-based targeting approaches can selectively deliver drugs to the site of inflammation and reduce the risk of side effects by decreasing systemic availability. Here, we developed a nanoparticulate platform for the delivery of the anti-TNF-α antibody adalimumab (ADA) by covalent crosslinking to the particle surface. ADA binding to nanoparticles improved the stability of ADA against proteolytic degradation in vitro and led to a significantly better therapeutic outcome in a murine colitis model. Moreover, immobilization of ADA reduced systemic exposure, which can lead to enhanced therapeutic safety. Thus, nanoparticle protein decoration constitutes a platform through which epithelial delivery of any biological of interest to the inflamed gut and hence a local treatment can be achieved.
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Affiliation(s)
- Markus Ries
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany; (M.R.); (M.A.S.B.); (M.E.A.)
| | - Brice Moulari
- PEPITE EA4276, University of Burgundy/Franche-Comté, 25030 Besançon, France; (B.M.); (A.B.); (Y.P.)
| | - Maryam A. Shetab Boushehri
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany; (M.R.); (M.A.S.B.); (M.E.A.)
| | - Mohamed Ehab Ali
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany; (M.R.); (M.A.S.B.); (M.E.A.)
| | - Daniel Molnar
- Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany;
| | - Arnaud Béduneau
- PEPITE EA4276, University of Burgundy/Franche-Comté, 25030 Besançon, France; (B.M.); (A.B.); (Y.P.)
| | - Yann Pellequer
- PEPITE EA4276, University of Burgundy/Franche-Comté, 25030 Besançon, France; (B.M.); (A.B.); (Y.P.)
| | - Alf Lamprecht
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, 53121 Bonn, Germany; (M.R.); (M.A.S.B.); (M.E.A.)
- PEPITE EA4276, University of Burgundy/Franche-Comté, 25030 Besançon, France; (B.M.); (A.B.); (Y.P.)
- Correspondence: ; Tel.: +49-228-735243; Fax: +49-228-735268
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Yu D, Zhao Y, Wang H, Kong D, Jin W, Hu Y, Qin Y, Zhang B, Li X, Hao J, Li G, Wang H. IL-1β pre-stimulation enhances the therapeutic effects of endometrial regenerative cells on experimental colitis. Stem Cell Res Ther 2021; 12:324. [PMID: 34090510 PMCID: PMC8180147 DOI: 10.1186/s13287-021-02392-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis. METHODS BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction. RESULTS It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation (p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs. CONCLUSIONS This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.
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Affiliation(s)
- Dingding Yu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yiming Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Wang Jin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yonghao Hu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Baoren Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China.,Department of Anorectal Surgery, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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11
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Zhang L, Ocansey DKW, Liu L, Olovo CV, Zhang X, Qian H, Xu W, Mao F. Implications of lymphatic alterations in the pathogenesis and treatment of inflammatory bowel disease. Biomed Pharmacother 2021; 140:111752. [PMID: 34044275 DOI: 10.1016/j.biopha.2021.111752] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/06/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by intense immune dysregulation, gut microbiota imbalance, and intestinal epithelium destruction. Among the factors that contribute to the pathogenesis of IBD, lymphatics have received less attention, hence less studied, characterized, and explored. However, in recent years, the role of the lymphatic system in gastrointestinal pathophysiology continues to be highlighted. This paper examines the implications of lymphatic changes in IBD pathogenesis related to immune cells, gut microbiota, intestinal and mesenteric epithelial barrier integrity, and progression to colorectal cancer (CRC). Therapeutic targets of lymphatics in IBD studies are also presented. Available studies indicate that lymph nodes and other secondary lymphatic tissues, provide highly specialized microenvironments for mounting effective immune responses and that lymphatic integrity plays a significant role in small intestine homeostasis, where the lymphatic vasculature effectively controls tissue edema, leukocyte exit, bacterial antigen, and inflammatory chemokine clearance. In IBD, there are functional and morphological alterations in intestinal and mesenteric lymphatic vessels (more profoundly in Crohn's disease [CD] compared to ulcerative colitis [UC]), including lymphangiogenesis, lymphangiectasia, lymphadenopathy, and lymphatic vasculature blockade, affecting not only immunity but gut microbiota and epithelial barrier integrity. While increased lymphangiogenesis is primarily associated with a good prognosis of IBD, increased lymphangiectasia, lymphadenopathy, and lymphatic vessel occlusion correlate with poor prognosis. IBD therapies that target the lymphatic system seek to increase lymphangiogenesis via induction of lymphangiogenic factors and inhibition of its antagonists. The resultant increased lymphatic flow coupled with other anti-inflammatory activities restores gut homeostasis.
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Affiliation(s)
- Lu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China; Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Lianqin Liu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Chinasa Valerie Olovo
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China; Department of Microbiology, University of Nigeria, Nsukka 410001, Nigeria
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China.
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12
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Lee SD, Shivashankar R, Quirk D, Zhang H, Telliez JB, Andrews J, Marren A, Mukherjee A, Loftus EV. Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments. J Clin Gastroenterol 2021; 55:195-206. [PMID: 32740098 PMCID: PMC7960149 DOI: 10.1097/mcg.0000000000001396] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4β7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.
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Affiliation(s)
- Scott D. Lee
- Digestive Health Center, University of Washington Medical Center, Seattle, WA
| | - Raina Shivashankar
- Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia
| | | | | | | | | | | | | | - Edward V. Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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13
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Ollech JE, Normatov I, Peleg N, Wang J, Patel SA, Rai V, Yi Y, Singer J, Dalal SR, Sakuraba A, Cohen RD, Rubin DT, Pekow J. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2021; 19:104-110. [PMID: 32109634 PMCID: PMC8665415 DOI: 10.1016/j.cgh.2020.02.035] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/25/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS A subset of patients with Crohn's disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses. METHODS We performed a retrospective study to determine the effectiveness of ustekinumab dose interval shortening, collecting data from 506 patients with CD who received subcutaneous ustekinumab 90 mg every 8 weeks at a single center. We obtained data from 110 patients who initially received subcutaneous ustekinumab 90 mg every 8 weeks and then had their interval shortened to every 4 weeks. Harvey Bradshaw Index (HBI) scores before and after the dose interval shortening was available for 78 patients in the cohort (71%), levels of C-reactive protein (CRP) for 60 patients (55%), and levels of fecal calprotectin for 8 patients (7%). RESULTS Following dose interval shortening, the patients' median HBI decreased from 4.5 to 3 (P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L (P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P = .57). Among patients who had an HBI >4, a level of CRP ≥5mg/dL, a level of fecal calprotectin >250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (<5 mg/dL), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission. CONCLUSIONS Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe.
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Affiliation(s)
- Jacob E. Ollech
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois,Inflammatory Bowel Disease Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel
| | - Inessa Normatov
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Noam Peleg
- Inflammatory Bowel Disease Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel
| | - Jingzhou Wang
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Shivani A. Patel
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Victoria Rai
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Yangtian Yi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Jorie Singer
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Sushila R. Dalal
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Russell D. Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - David T. Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
| | - Joel Pekow
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois
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14
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Evaluation of two point of care technologies for measuring monoclonal antibody therapeutic-A concentrations in blood. Bioanalysis 2020; 12:1449-1458. [PMID: 32975432 DOI: 10.4155/bio-2020-0193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim: Current blood monitoring methods require sample collection and testing at a central lab, which can take days. Point of care (POC) devices with quick turnaround time can provide an alternative with faster results, allowing for real-time data leading to better treatment decisions for patients. Results/Methodology: An assay to measure monoclonal antibody therapeutic-A was developed on two POC devices. Data generated using 75 serum samples (65 clinical & ten spiked samples) show correlative results to the data generated using Gyrolab technology. Conclusion: This case study uses a monoclonal antibody therapeutic-A concentration assay as an example to demonstrate the potential of POC technologies as a viable alternative to central lab testing with quick results allowing for real-time decision-making.
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15
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Sahnan K, Adegbola SO, Fareleira A, Hart A, Warusavitarne J. Medical-surgical Combined Approach in Perianal Fistulizing Crohn's Disease (CD): Doing it Together. Curr Drug Targets 2020; 20:1373-1383. [PMID: 31109272 DOI: 10.2174/1389450120666190520103454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/13/2019] [Accepted: 04/17/2019] [Indexed: 02/08/2023]
Abstract
Fistulising perianal Crohn's disease (pCD) is an aggressive phenotype, and patients not only suffer from perianal manifestations but also a worsening course for their luminal disease. This article describes the 6 key steps clinicians need to consider when managing patients with pCD which include; (i) ensuring a prompt diagnosis, (ii) multi-disciplinary management, (iii) psychological support, (iv) using multimodal medical and surgical treatment strategies, (v) continually monitoring and optimising therapy and (vi) ensuring that patients have a way of accessing care if required. Patients with fistulising pCD often have an unpredictable disease course and complete remission can be elusive. As such, a considered and nuanced approach is essential keeping the wider multi-disciplinary team and the patient involved in all decision making.
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Affiliation(s)
- Kapil Sahnan
- Robin Phillips' Fistula Research Unit, St. Mark's Hospital, Harrow, United Kingdom.,Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Samuel O Adegbola
- Robin Phillips' Fistula Research Unit, St. Mark's Hospital, Harrow, United Kingdom.,Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | | | - Ailsa Hart
- Robin Phillips' Fistula Research Unit, St. Mark's Hospital, Harrow, United Kingdom.,Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Janindra Warusavitarne
- Robin Phillips' Fistula Research Unit, St. Mark's Hospital, Harrow, United Kingdom.,Department of Surgery and Cancer, Imperial College, London, United Kingdom
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16
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Morita Y, Imai T, Bamba S, Takahashi K, Inatomi O, Miyazaki T, Watanabe K, Nakamura S, Yoshida A, Endo Y, Ohmiya N, Tsujikawa T, Andoh A. Clinical relevance of innovative immunoassays for serum ustekinumab and anti-ustekinumab antibody levels in Crohn's disease. J Gastroenterol Hepatol 2020; 35:1163-1170. [PMID: 31860733 DOI: 10.1111/jgh.14962] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Ustekinumab is a human monoclonal antibody to the p40 subunit of human IL-12/IL-23. The purpose of this report is to verify the newly developed immunoassays for serum ustekinumab and anti-ustekinumab antibody (AUA) concentrations and assess their clinical utility. METHODS Serum ustekinumab trough levels and AUA levels were measured using new immunoassays in 38 patients with Crohn's disease under ustekinumab maintenance injection. RESULTS Mean ustekinumab trough levels were 2.54 ± 2.1 μg/mL, and 3 of 38 patients (7.9%) were positive for AUAs. There was no association between ustekinumab trough levels and AUA levels. The optimal trough level of ustekinumab to maintain negative C-reactive protein levels (≤ 0.3 mg/dL) was 1.67 μg/mL determined by receiver operating characteristic curve analysis. Ustekinumab trough level negatively but significantly correlated with C-reactive protein, erythrocyte sedimentation rate, and Crohn's disease activity index and positively and significantly correlated with serum albumin levels. Ustekinumab trough levels were significantly higher in biologics-naïve patients than in biologics-experienced patients, although there was no difference in AUA levels. CONCLUSIONS We developed new assays for serum ustekinumab trough and AUA levels. These assays might provide new insights into therapeutic drug monitoring-based management of Crohn's disease patients under ustekinumab therapy.
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Affiliation(s)
- Yasuhiro Morita
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Takayuki Imai
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Shigeki Bamba
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Japan
| | | | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Takako Miyazaki
- Department of Intestinal Inflammation Research, Hyogo College of Medicine, Hyogo, Japan
| | - Kenji Watanabe
- Department of Intestinal Inflammation Research, Hyogo College of Medicine, Hyogo, Japan
| | - Shiro Nakamura
- Department of Intestinal Inflammation Research, Hyogo College of Medicine, Hyogo, Japan
| | - Atsushi Yoshida
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kamakura, Japan
| | - Yutaka Endo
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kamakura, Japan
| | - Naoki Ohmiya
- Department of Gastroenterology, Fujita Health University School of Medicine, Nagoya, Japan
| | - Tomoyuki Tsujikawa
- Department of Gastroenterology, National Hospital Organization Higashi-Ohmi General Medical Center, Higashi-Ohmi, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
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17
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Costrini NV. Clearing of the Clouds in Inflammatory Bowel Disease Management. Dig Dis Sci 2020; 65:3411-3417. [PMID: 33009978 PMCID: PMC7532337 DOI: 10.1007/s10620-020-06635-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/22/2020] [Indexed: 12/26/2022]
Abstract
The skies over inflammatory bowel disease care are beginning to clear. Success is being achieved in the management of inflammatory bowel disease due to ongoing research, new medications, and most significantly to the recognition of the importance of patient selection and the definition of remission. Five answered questions provide the basis for recent successes and forecast for clearing of the clouds. How do we classify the inflammatory bowel disease (IBD) patient? How do we select our medications to best match the patients' classifications? How do we monitor and manage medications during the course of care? How can we predict the likelihood of response to a selected medication? Besides medications and surgery, what else is needed for best care in 2020 and beyond? These questions are addressed in this communication.
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Affiliation(s)
- Nicholas V. Costrini
- grid.255986.50000 0004 0472 0419Florida State University College of Medicine, Tallahassee, FL USA
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18
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Khoury T, Ilan Y. Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies. Front Immunol 2019; 10:2726. [PMID: 31824506 PMCID: PMC6879658 DOI: 10.3389/fimmu.2019.02726] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/06/2019] [Indexed: 12/18/2022] Open
Abstract
Primary lack of response and secondary loss of response (LOR) are major obstacles to the use of anti-tumor necrosis factor (TNF)-based therapies in patients with rheumatoid arthritis or inflammatory bowel disease. Here, we review the mechanisms and methods for predicting LOR and the currently used methods for overcoming the ineffectiveness of anti-TNFs. The complex functions of TNF and anti-TNF antibodies, which can promote both pro- or anti-inflammatory actions, and the factors that affect the induction of immune tolerance to their effects are presented. The lack of rules and the continuous dynamics of the immune processes partly underlie the unpredictability of the response to anti-TNFs. Variability is inherent to biological systems, including immune processes, and intra/inter-patient variability has been described in the response to drugs. This variability is viewed as a compensatory adaptation mechanism of the immune system in response to drugs and may contribute to treatment LOR. Dose reductions and drug holidays have been tested in patients treated with anti-TNFs. Regular dose-based regimens may be incompatible with physiological variability, further contributing to treatment inefficacy. We present the concept of overcoming immune system adaptation to anti-TNFs by introducing patient-tailored patterns of variability to treatment regimens.
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Affiliation(s)
- Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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19
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Hemperly A, Vande Casteele N. Clinical Pharmacokinetics and Pharmacodynamics of Infliximab in the Treatment of Inflammatory Bowel Disease. Clin Pharmacokinet 2019; 57:929-942. [PMID: 29330783 DOI: 10.1007/s40262-017-0627-0] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Infliximab was the first monoclonal antibody to be approved for the treatment of pediatric and adult patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC). It has been shown to induce and maintain both clinical remission and mucosal healing in pediatric and adult patients with inflammatory bowel disease (IBD) who are unresponsive or refractory to conventional therapies. The administration of infliximab is weight-based and the drug is administered intravenously. The volume of distribution of infliximab is low and at steady state ranges from 4.5 to 6 L. Therapeutic monoclonal antibodies, such as immunoglobulins, are cleared from the circulation primarily by catabolism. Median infliximab half-life is approximately 14 days. Infliximab concentration-time data in patients with CD and UC have been shown to be highly variable within an individual patient over time and between individuals by multiple population pharmacokinetic models. Covariates that have been identified to account for a part of the observed inter- and intra-individual variability in clearance are the presence of antidrug antibodies, use of concomitant immunomodulators, degree of systemic inflammation, serum albumin concentration, and body weight, which can affect the pharmacodynamic response. This article provides a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of infliximab, as well as the role of therapeutic drug monitoring in the treatment of IBD.
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Affiliation(s)
- Amy Hemperly
- Department of Pediatric Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Niels Vande Casteele
- Department of Medicine, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA.
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20
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Daperno M, Armuzzi A, Danese S, Fries W, Liguori G, Orlando A, Papi C, Principi M, Rizzello F, Viscido A, Gionchetti P. Unmet Medical Needs in the Management of Ulcerative Colitis: Results of an Italian Delphi Consensus. Gastroenterol Res Pract 2019; 2019:3108025. [PMID: 31565051 PMCID: PMC6745180 DOI: 10.1155/2019/3108025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The lifelong and remitting nature of ulcerative colitis results in considerable disability and a substantial negative impact on quality of life. The major goal of the therapy of ulcerative colitis is considered to be the modification of the course of the disease, so that the patient's quality of life can be improved while minimising disease-related disability. Although considerable progress in understanding the molecular pathways involved in ulcerative colitis has led to improved treatment options, there is currently no definitive cure for ulcerative colitis, there remain considerable unmet needs in terms of long-term efficacy and safety, and there are many patients who continue to be burdened by physical and psychological symptoms. Defining unmet needs can help to increase the awareness of the shortcomings of current therapeutic management and highlight the need to achieve not only a control of clinical symptoms but also control of mucosal healing, in order to attain the best possible long-term outcomes. METHODS With the aim of providing a better understanding of the unmet needs of patients towards improving overall care, a Delphi process was used to obtain consensus among a group of Italian ulcerative colitis experts. The consensus group met with a major focus of delineating the unmet needs of current treatment strategies and overall management of ulcerative colitis, while also focusing on quality of life and patient care. RESULTS Three main areas were identified: (i) treatment, (ii) monitoring and risk management, and (iii) patient-related issues. A high level of consensus was reached on all but one of the statements identified. CONCLUSIONS The findings arising from the Delphi process provide valuable insights into the unmet needs in the management of moderate-to-severe ulcerative colitis from the clinician's perspective, while emphasising the benefits of therapeutic individualization and suggesting areas that need additional study with the aim of optimising the treatment of patients with ulcerative colitis.
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Affiliation(s)
- Marco Daperno
- Gastroenterology Unit, Mauriziano Hospital, Turin, Italy
| | - Alessandro Armuzzi
- IBD Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Walter Fries
- Clinical Unit for Chronic Bowel Disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | | | - Ambrogio Orlando
- IBD Unit, Division of Internal Medicine, “Villa Sofia-Cervello” Hospital, Palermo, Italy
| | | | - Mariabeatrice Principi
- Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari 70124, Italy
| | - Fernando Rizzello
- IBD Unit, Department of Medicine and Surgery (DIMEC), University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Angelo Viscido
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paolo Gionchetti
- IBD Unit, Department of Medicine and Surgery (DIMEC), University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
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21
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Moore L. The IBD Management Puzzle: Do We Have All the Pieces? EUROPEAN MEDICAL JOURNAL 2019. [DOI: 10.33590/emj/10314245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The management of inflammatory bowel disease (IBD) has entered an exciting era, with the optimisation of existing therapies, new strategies being explored that have the potential to further improve patient outcomes, and a growing recognition of the value of a personalised approach to treatment. This symposium explored optimal approaches to using biologic therapy, and the use of therapeutic drug monitoring (TDM) and biomarkers in treatment management.
IBD shows a progressive immunopathogenesis, and a ‘window of opportunity’ exists whereby early intervention may alter the disease course. There is a convincing body of evidence supporting early intervention with anti-TNF-α therapies to improve patient outcomes. Cost is the major barrier to initiating and continuing treatment with biologic therapy. Biosimilars have the potential to reduce costs and increase patient access to biologic therapies, enabling more patients to receive biologic treatment earlier. The use of TDM in the treatment of IBD is increasing and offers benefits over standardised approaches to dosing, and it is likely that emerging dose optimisation tools will enable a personalised approach to treatment in the future.
Many patients experience loss of response to anti-TNF-α therapy. Biomarkers currently used to monitor treatment response include C reactive protein (CRP), faecal calprotectin, and anti-drug antibodies (ADA). Although biomarker identification is still at an early stage for IBD, several genetic, serological, and microbiome markers have also shown promise in predicting response to anti-TNF-α therapy, while other biomarkers are also under investigation for use in diagnosis, predicting response to therapy, and treatment monitoring.
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22
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Gomes LEM, da Silva FAR, Pascoal LB, Ricci RL, Nogueira G, Camargo MG, de Lourdes Setsuko Ayrizono M, Fagundes JJ, Leal RF. Serum Levels of Infliximab and Anti-Infliximab Antibodies in Brazilian Patients with Crohn's Disease. Clinics (Sao Paulo) 2019; 74:e824. [PMID: 30994711 PMCID: PMC6445154 DOI: 10.6061/clinics/2019/e824] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 11/28/2018] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVES The aim of this study was to evaluate the quantitative serum level of infliximab (IFX) as well as the detection of anti-infliximab antibodies (ATIs) in patients with Crohn's disease (CD). METHOD Forty patients with CD under treatment at a tertiary center in southeastern Brazil were evaluated. Their use of infliximab was continuous and regular. We analyzed and compared the differences in the IFX and ATI levels between the patients with active CD (CDA) and those with CD in remission (CDR). RESULTS There was no difference in the IFX level between the CDA and CDR groups (p>0.05). Eighty percent of all patients had IFX levels above the therapeutic concentration (6-10 μg/mL). Two (9%) of the 22 patients with active disease and four (22.2%) of the 18 patients in remission had undetectable levels of IFX. Four (66.6%) of the six patients with undetectable levels of IFX had positive ATI levels; three of these patients were in remission, and one had active disease. In addition, the other two patients with undetectable levels of IFX presented ATI levels close to positivity (2.7 and 2.8 AU/ml). None of the patients with therapeutic or supratherapeutic IFX levels had positive ATI levels. CONCLUSIONS The undetectable levels of IFX correlated with the detection of ATIs, which was independent of disease activity. Immunogenicity was not the main factor for the loss of response to IFX in our study, and the majority of patients in both groups (CDA and CDR) had supratherapeutic levels of IFX.
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Affiliation(s)
- Luis Eduardo Miani Gomes
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Francesca Aparecida Ramos da Silva
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Lívia Bitencourt Pascoal
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Renato Lazarin Ricci
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Guilherme Nogueira
- Laboratorio de Sinalizacao Celular, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Michel Gardere Camargo
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Maria de Lourdes Setsuko Ayrizono
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - João José Fagundes
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Raquel Franco Leal
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
- Corresponding author. E-mail:
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23
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Osterman MT, Rosario M, Lasch K, Barocas M, Wilbur JD, Dirks NL, Gastonguay MR. Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation. Aliment Pharmacol Ther 2019; 49:408-418. [PMID: 30663076 PMCID: PMC6590294 DOI: 10.1111/apt.15113] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/17/2018] [Accepted: 12/06/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prospectively designed studies assessing the exposure-response profile of vedolizumab are lacking. Observational exposure-response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance. AIMS To (a) investigate the vedolizumab exposure-response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short- and long-term clinical outcomes in adults with ulcerative colitis in GEMINI 1. METHODS Propensity-score-based case-matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti-tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated. RESULTS Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52. CONCLUSIONS In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short- and long-term remission. Potential induction and maintenance target concentrations were proposed for further study.
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Affiliation(s)
- Mark T. Osterman
- Division of GastroenterologyUniversity of Pennsylvania Perelman School of Medicine, Penn Presbyterian Medical CenterPhiladelphiaPennsylvania
| | - Maria Rosario
- Takeda Pharmaceuticals International IncCambridgeMassachusetts
| | - Karen Lasch
- Takeda Pharmaceuticals USA, IncDeerfieldIllinois
| | - Morris Barocas
- Takeda Pharmaceuticals USA, IncDeerfieldIllinois,Present address:
PRA Health SciencesRaleighNorth Carolina
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Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol 2018; 11:1558-1570. [PMID: 29907872 PMCID: PMC6279599 DOI: 10.1038/s41385-018-0050-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/15/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023]
Abstract
The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.
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Affiliation(s)
- Sudarshan Paramsothy
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adam K. Rosenstein
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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25
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Nencini F, Vultaggio A, Pratesi S, Cammelli D, Milla M, Fiori G, Bagnoli S, Prignano F, Romagnani S, Maggi E, Matucci A. The Kinetics of Antidrug Antibodies, Drug Levels, and Clinical Outcomes in Infliximab-Exposed Patients with Immune-Mediated Disorders. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 6:2065-2072.e2. [DOI: 10.1016/j.jaip.2018.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 03/15/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023]
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26
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Anti-TNF Therapy in Crohn's Disease. Int J Mol Sci 2018; 19:ijms19082244. [PMID: 30065229 PMCID: PMC6121417 DOI: 10.3390/ijms19082244] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/04/2018] [Accepted: 07/07/2018] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) accounts for a variety of clinical manifestations or phenotypes that stem from chronic inflammation in the gastrointestinal tract. Its worldwide incidence is increasing including younger or childhood-onset of disease. The natural history of Crohn’s disease is characterized by a remitting and relapsing course that progresses to complications and surgery in most patients. The goals of treatment are to achieve clinical and endoscopic remission, to avoid disease progression and minimise surgical resections. Medical treatment usually features antibiotics, corticosteroids, immunomodulators (thiopurines, methotrexate). Anti-TNF (tumour necrosis factor) therapy was approved for use in Crohn’s disease in 1998, and has changed the paradigm of treatment, leading to improved rates of response and remission in patients. There are significant considerations that need to be borne in mind, when treating patients including immunogenicity, safety profile and duration of treatment.
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27
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Abstract
AIM Etanercept has shown to mediate a favorable effect on immune-mediated inflammatory diseases (IMID), including plaque psoriasis. Therapeutic drug monitoring (TDM) of etanercept could improve clinical outcome and cost-effectiveness. A high intrapatient variability (IPV) of etanercept trough concentrations at standard dosing would reduce the feasibility of therapeutic drug monitoring. Studies have focused on the interpatient differences associated with the exposure to biologics. The aim of this study was to determine IPV of etanercept and correlate etanercept trough concentrations and IPV with treatment response. METHODS Repetitive serum samples of 29 psoriasis patients on standard etanercept maintenance treatment were collected. In these samples, etanercept trough concentrations were determined and IPV was assessed in relation to response to treatment. RESULTS The median IPV of etanercept trough concentrations was 33.7% (Q1 = 21.3% and Q3 = 51.7%) ranging from 8% to 155%. All 6 nonresponders showed an IPV at or above the median value of 33.7%. The 6 nonresponders showed a higher IPV as compared to the 23 responders (53.9% versus 24.2%; P = 0.031). The mean etanercept trough concentration for each patient ranged from 0.7 to 6.8 mcg/mL, with a median trough concentration of 2.7 mcg/mL. Patients with an IPV above the median had lower mean etanercept trough concentrations compared to patients with an IPV below the median (1.96 mcg/mL, 95% CI, 1.7-2.4 versus 3.2 mcg/mL, 95% CI, 2.7-4.0; P = 0.001). CONCLUSIONS The median IPV of etanercept trough concentrations in this study population was 33.7%. A higher IPV was correlated with lower etanercept trough concentrations and with nonresponsiveness. Prospective trials are required to demonstrate the value of adjusting the etanercept dose based on drug trough concentrations. The relatively high IPV observed in this study may complicate therapeutic drug monitoring.
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28
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Adegbola SO, Pisani A, Sahnan K, Tozer P, Ellul P, Warusavitarne J. Medical and surgical management of perianal Crohn's disease. Ann Gastroenterol 2018; 31:129-139. [PMID: 29507460 PMCID: PMC5825943 DOI: 10.20524/aog.2018.0236] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/24/2017] [Indexed: 12/16/2022] Open
Abstract
Crohn's disease is increasingly thought to encompass multiple possible phenotypes. Perianal manifestations account for one such phenotype and represent an independent disease modifier. In its more severe form, perianal Crohn's disease confers a higher risk of a severe and disabling disease course, relapses, hospital admissions and operations. This, in turn, imposes a considerable burden and disability on patients. Identification of the precise manifestation is important, as management is nuanced, with both medical and surgical components, and is best undertaken in a multidisciplinary setting for both diagnosis and ongoing treatment. The introduction of biologic medication has heralded a significant addition to the management of fistulizing perianal Crohn's disease in particular, albeit with modest results. It remains a very challenging condition to treat and further work is required to optimize management in this group of patients.
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Affiliation(s)
- Samuel O. Adegbola
- Department of Colorectal Surgery St. Mark’s Hospital, Harrow, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phil Tozer, Janindra Warusavitarne)
- Department of Surgery and Cancer, Imperial College, London, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phillip Tozer, Janindra Warusavitarne)
| | - Anthea Pisani
- Department of Gastroenterology, Mater dei Hospital, Malta (Pierre Ellul)
| | - Kapil Sahnan
- Department of Colorectal Surgery St. Mark’s Hospital, Harrow, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phil Tozer, Janindra Warusavitarne)
- Department of Surgery and Cancer, Imperial College, London, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phillip Tozer, Janindra Warusavitarne)
| | - Phil Tozer
- Department of Colorectal Surgery St. Mark’s Hospital, Harrow, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phil Tozer, Janindra Warusavitarne)
- Department of Surgery and Cancer, Imperial College, London, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phillip Tozer, Janindra Warusavitarne)
| | - Pierre Ellul
- Department of Gastroenterology, Mater dei Hospital, Malta (Pierre Ellul)
| | - Janindra Warusavitarne
- Department of Colorectal Surgery St. Mark’s Hospital, Harrow, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phil Tozer, Janindra Warusavitarne)
- Department of Surgery and Cancer, Imperial College, London, United Kingdom (Samuel O. Adegbola, Kapil Sahnan, Phillip Tozer, Janindra Warusavitarne)
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29
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Thery-Casari C, Jamilloux Y, Bouvry D, Chapelon-Abric C, Marquet A, Bielefeld P, Schleinitz N, Vukusic S, Girszyn N, Fain O, Bonnet F, Valeyre D, Seve P. Outcome of patients with sarcoidosis refractory to TNF antagonists: a case series. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2018; 35:371-375. [PMID: 32476925 PMCID: PMC7170127 DOI: 10.36141/svdld.v35i4.6999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 02/06/2018] [Indexed: 11/25/2022]
Abstract
Background: Tumor necrosis factor (TNF) antagonists have been reported as an efficient third-line therapy for sarcoidosis but there is no data regarding patients who do not respond to this treatment. Objective: To report the characteristics, the outcome and the response to therapy of patients with sarcoidosis resistant to TNF antagonists. Methods: Patients from the French STAT (Sarcoidosis Treatment with Anti-TNF) registry who were classified as non-responders and who were followed-up for >1 year were included. The response to further therapies was classified as complete response, or partial response, and the others were classified as non-responders. Results: Among the 132 patients from the registry, 14 were considered as non-responders to anti-TNF. Nine patients (66% of women; mean age 48 years) were analyzed. The mean number of organs involved was 4.2. Seven patients were previously treated with more than 2 immunosuppressive treatments. The mean duration of the anti-TNF treatment was 9 months (range, 3-24). After a mean follow-up duration of 58 months (median, 35; range, 19-128) a complete response was observed in 2/9 cases, a partial response in 5/9 cases, and 2/9 cases were considered as non-responders. In all but one patient, the immunosuppressant that allowed the clinical response had previously been used. Furthermore, the dosage was not necessarily increased to gain efficacy. Non-responders were treated by corticosteroids only because of their comorbidities or noncompliance. Conclusion: In patients who do not respond to TNF antagonists, previously used immunosuppressants may be useful. Excluding a differential diagnosis, assessing compliance and testing for anti-drug antibodies should be systematic. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 371-375)
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Affiliation(s)
- Clémence Thery-Casari
- Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Yvan Jamilloux
- Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Diane Bouvry
- Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France
| | - Catherine Chapelon-Abric
- Service de Médecine Interne et d'Immunologie Clinique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Alicia Marquet
- Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Philip Bielefeld
- Service de Médecine Interne, Centre Hospitalier Universitaire de Dijon, Dijon, France
| | - Nicolas Schleinitz
- Service de Médecine Interne, Hôpital de le Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France
| | - Sandra Vukusic
- Service de Neurologie, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Nicolas Girszyn
- Service de Médecine Interne, Centre Hospitalier Universitaire de Rouen, Rouen, France
| | - Olivier Fain
- Service de Médecine Interne, Centre Hospitalier Universitaire Saint Antoine, Assistance Publique-Hôpitaux de Paris, Université Paris 6, Paris, France
| | - Fabrice Bonnet
- Service de Médecine Interne et de Maladies Infectieuses Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Dominique Valeyre
- Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France
| | - Pascal Seve
- Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, Université Claude Bernard Lyon 1, Villeurbanne, France
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van Hoeve K, Hoffman I, Vermeire S. Therapeutic drug monitoring of anti-TNF therapy in children with inflammatory bowel disease. Expert Opin Drug Saf 2017; 17:185-196. [PMID: 29202588 DOI: 10.1080/14740338.2018.1413090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Karen van Hoeve
- Department of Pediatric Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Ilse Hoffman
- Department of Pediatric Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
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31
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Kothari MM, Nguyen DL, Parekh NK. Strategies for overcoming anti-tumor necrosis factor drug antibodies in inflammatory bowel disease: Case series and review of literature. World J Gastrointest Pharmacol Ther 2017; 8:155-161. [PMID: 28828193 PMCID: PMC5547373 DOI: 10.4292/wjgpt.v8.i3.155] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/14/2017] [Accepted: 06/07/2017] [Indexed: 02/06/2023] Open
Abstract
Anti-tumor necrosis factor (TNF) biologics are currently amongst the most widely used and efficacious therapies for inflammatory bowel disease (IBD). The development of therapeutic drug monitoring for infliximab and adalimumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients (75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.
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32
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Osterman MT, Lichtenstein GR. Infliximab vs Adalimumab for UC: Is There A Difference? Clin Gastroenterol Hepatol 2017; 15:1197-1199. [PMID: 28479503 DOI: 10.1016/j.cgh.2017.04.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Mark T Osterman
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Gary R Lichtenstein
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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33
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Ward MG, Warner B, Unsworth N, Chuah SW, Brownclarke C, Shieh S, Parkes M, Sanderson JD, Arkir Z, Reynolds J, Gibson PR, Irving PM. Infliximab and adalimumab drug levels in Crohn's disease: contrasting associations with disease activity and influencing factors. Aliment Pharmacol Ther 2017; 46:150-161. [PMID: 28481014 DOI: 10.1111/apt.14124] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 01/24/2017] [Accepted: 04/09/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Discriminative drug level thresholds for disease activity endpoints in patients with Crohn's disease. have been consistently demonstrated with infliximab, but not adalimumab. AIMS To identify threshold concentrations for infliximab and adalimumab in Crohn's disease according to different disease endpoints, and factors that influence drug levels. METHODS We performed a cross-sectional service evaluation of patients receiving maintenance infliximab or adalimumab for Crohn's disease. Serum drug levels were at trough for infliximab and at any time point for adalimumab. Endpoints included Harvey-Bradshaw index, C-reactive protein and faecal calprotectin. 6-tioguanine nucleotide (TGN) concentrations were measured in patients treated with thiopurines. RESULTS A total of 191 patients (96 infliximab, 95 adalimumab) were included. Differences in infliximab levels were observed for clinical (P=.081) and biochemical remission (P=.003) and faecal calprotectin normalisation (P<.0001) with corresponding thresholds identified on ROC analysis of 1.5, 3.4 and 5.7 μg/mL. Adalimumab levels were similar between active disease and remission regardless of the endpoint assessed. Modelling identified that higher infliximab dose, body mass index and colonic disease independently accounted for 31% of the variation in infliximab levels, and weekly dosing, albumin and weight accounted for 23% of variation in adalimumab levels. TGN levels did not correlate with drug levels. CONCLUSIONS Infliximab drug levels are associated with the depth of response/remission in patients with Crohn's disease, but no such relationship was observed for adalimumab. More data are needed to explain the variation in drug levels.
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Affiliation(s)
- M G Ward
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.,Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - B Warner
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - N Unsworth
- Reference Chemistry, Viapath, St. Thomas' Hospital, London, UK
| | - S-W Chuah
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - C Brownclarke
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - S Shieh
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - M Parkes
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - J D Sanderson
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Z Arkir
- Reference Chemistry, Viapath, St. Thomas' Hospital, London, UK
| | - J Reynolds
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - P R Gibson
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - P M Irving
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
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34
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Rubin DT, Naik S, Kondragunta V, Rao T, Jain A. Detection of adalimumab and antibodies to adalimumab using a homogeneous mobility shift assay. Curr Med Res Opin 2017; 33:837-843. [PMID: 28145781 DOI: 10.1080/03007995.2017.1289908] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE In 2013 a novel commercial test was launched (Anser 1 ADA test) for the assay of serum adalimumab (ADL) and antibodies to adalimumab (ATA). This study aims to understand clinical practice patterns used with ADL in a real-world cross-sectional population. METHODS Wilcoxon rank sum test, and linear and logistic regression methods were applied in the statistical analysis to test hypotheses. The study design was observational and uncontrolled. RESULTS Of a total of 14,239 tests conducted, 5509 had information available that pertained to reasons for ordering, of which disease monitoring (46.9%) was the most common. Median serum ADL level with standard maintenance dosing (40 mg, biweekly) was 8.8 μg/mL (n = 2901). A five-fold decrease in median serum ADL levels occurred with very low ATA titers (1.7-3 U/mL, p < .0001). Serum ADL levels decreased further with ATA >7 U/mL (p < .0001). A total of 16.5% of patients were ATA positive, of whom 61.9% had low ATA (1.7-7 U/mL); 87.9% of ATA-positive patients had serum ADL levels ≤4.4 μg/mL. Expression of inflammatory markers significantly increased with high ATA (>7 U/mL). An inverse relationship between ADL and ATA was observed (R2: 0.49), and 4.1 μg/mL was identified as a cut-off that may segregate ATA-positive patients. CONCLUSION In this real-world cross-sectional population, serum ADL levels decreased with increasing ATA titers, with low ATA titers (≤7 U/mL) significantly reducing serum ADL compared to ATA-negative samples. Expression of inflammatory markers significantly increased at higher ATA titers (>7 U/mL). These findings highlight the clinical importance of monitoring patients for drug levels and anti-drug antibody titers.
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Affiliation(s)
- David T Rubin
- a University of Chicago Medicine , Chicago , IL , USA
| | - Snehal Naik
- b Clinical Development and Medical Affairs , Prometheus Laboratories Inc. , San Diego , CA , USA
| | | | - Tharak Rao
- b Clinical Development and Medical Affairs , Prometheus Laboratories Inc. , San Diego , CA , USA
| | - Anjali Jain
- b Clinical Development and Medical Affairs , Prometheus Laboratories Inc. , San Diego , CA , USA
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Robinson AM, Rahman AA, Miller S, Stavely R, Sakkal S, Nurgali K. The neuroprotective effects of human bone marrow mesenchymal stem cells are dose-dependent in TNBS colitis. Stem Cell Res Ther 2017; 8:87. [PMID: 28420434 PMCID: PMC5395912 DOI: 10.1186/s13287-017-0540-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 03/14/2017] [Accepted: 03/17/2017] [Indexed: 02/08/2023] Open
Abstract
Background The incidence of inflammatory bowel diseases (IBD) is increasing worldwide with patients experiencing severe impacts on their quality of life. It is well accepted that intestinal inflammation associates with extensive damage to the enteric nervous system (ENS), which intrinsically innervates the gastrointestinal tract and regulates all gut functions. Hence, treatments targeting the enteric neurons are plausible for alleviating IBD and associated complications. Mesenchymal stem cells (MSCs) are gaining wide recognition as a potential therapy for many diseases due to their immunomodulatory and neuroprotective qualities. However, there is a large discrepancy regarding appropriate cell doses used in both clinical trials and experimental models of disease. We have previously demonstrated that human bone marrow MSCs exhibit neuroprotective and anti-inflammatory effects in a guinea-pig model of 2,4,6-trinitrobenzene-sulfonate (TNBS)-induced colitis; but an investigation into whether this response is dose-dependent has not been conducted. Methods Hartley guinea-pigs were administered TNBS or sham treatment intra-rectally. Animals in the MSC treatment groups received either 1 × 105, 1 × 106 or 3 × 106 MSCs by enema 3 hours after induction of colitis. Colon tissues were collected 72 hours after TNBS administration to assess the effects of MSC treatments on the level of inflammation and damage to the ENS by immunohistochemical and histological analyses. Results MSCs administered at a low dose, 1 × 105 cells, had little or no effect on the level of immune cell infiltrate and damage to the colonic innervation was similar to the TNBS group. Treatment with 1 × 106 MSCs decreased the quantity of immune infiltrate and damage to nerve processes in the colonic wall, prevented myenteric neuronal loss and changes in neuronal subpopulations. Treatment with 3 × 106 MSCs had similar effects to 1 × 106 MSC treatments. Conclusions The neuroprotective effect of MSCs in TNBS colitis is dose-dependent. Increasing doses higher than 1 × 106 MSCs demonstrates no further therapeutic benefit than 1 × 106 MSCs in preventing enteric neuropathy associated with intestinal inflammation. Furthermore, we have established an optimal dose of MSCs for future studies investigating intestinal inflammation, the enteric neurons and stem cell therapy in this model.
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Affiliation(s)
- Ainsley M Robinson
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia
| | - Ahmed A Rahman
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia
| | - Sarah Miller
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia
| | - Rhian Stavely
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia
| | - Samy Sakkal
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia
| | - Kulmira Nurgali
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.
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Battat R, Deol N, Nguyen TM, Parker CE, Khanna R, Feagan BG, Jairath V. Infliximab for maintenance of remission in Crohn's disease. Hippokratia 2017. [DOI: 10.1002/14651858.cd012609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Robert Battat
- Jewish General Hospital; Division of Gastroenterology; Montreal Quebec Canada
- McGill University Health Centre; Division of Gastroenterology; Montreal Canada
| | - Navjot Deol
- University of Western Ontario; Department of Medicine; London Ontario Canada
| | - Tran M Nguyen
- Robarts Clinical Trials; Cochrane IBD Group; 100 Dundas Street, Suite 200 London ON Canada
| | - Claire E Parker
- Robarts Clinical Trials; 100 Dundas Street, Suite 200 London ON Canada N6A 5B6
| | - Reena Khanna
- University of Western Ontario; Department of Medicine; London Ontario Canada
- Robarts Clinical Trials; 100 Dundas Street, Suite 200 London ON Canada N6A 5B6
| | - Brian G Feagan
- University of Western Ontario; Department of Medicine; London Ontario Canada
- Robarts Clinical Trials; Cochrane IBD Group; 100 Dundas Street, Suite 200 London ON Canada
- Robarts Clinical Trials; 100 Dundas Street, Suite 200 London ON Canada N6A 5B6
- University of Western Ontario; Department of Epidemiology and Biostatistics; London ON Canada
| | - Vipul Jairath
- University of Western Ontario; Department of Medicine; London Ontario Canada
- Robarts Clinical Trials; 100 Dundas Street, Suite 200 London ON Canada N6A 5B6
- University of Western Ontario; Department of Epidemiology and Biostatistics; London ON Canada
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Serum-Infliximab Trough Levels in 45 Children with Inflammatory Bowel Disease on Maintenance Treatment. Int J Mol Sci 2017; 18:ijms18030575. [PMID: 28272355 PMCID: PMC5372591 DOI: 10.3390/ijms18030575] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/22/2017] [Accepted: 02/27/2017] [Indexed: 01/19/2023] Open
Abstract
The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in a pediatric inflammatory bowel disease (IBD) cohort. We investigated the s-IFX trough levels in pediatric IBD patients (n = 45) on maintenance IFX treatment. Ninety-three blood samples were collected and demographics, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin were recorded. The mean s-IFX trough level was 5.2 µg/mL. The mean trough s-IFX level was significantly higher in the samples taken during remission (7.2 µg/mL) compared to active disease (4.5 µg/mL, p < 0.05). The trough s-IFX levels correlated with ESR, CRP, and albumin. S-IFX was undetectable in eight of the patients, all with positive ATI and active disease. Surprisingly, clinical and biochemical remission was observed at only 26 of the 93 visits. The correlation between dose variations and changes in trough s-IFX was not evident. In line with studies in adults, the s-IFX trough levels correlated with response to infliximab.
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Feagan BG, Rubin DT, Danese S, Vermeire S, Abhyankar B, Sankoh S, James A, Smyth M. Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2017; 15:229-239.e5. [PMID: 27639327 DOI: 10.1016/j.cgh.2016.08.044] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/05/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4β7, were demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti-tumor necrosis factor-α (TNF) antagonists. METHODS We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations. RESULTS At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4-40.4; RR, 2.0; 95% CI, 1.3-3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8-33.5; RR, 1.9; 95% CI, 1.1-3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9-41.1; RR, 2.5; 95% CI, 1.5-4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8-46.1; RR, 6.6; 95% CI, 1.7-26.5). No differences in adverse events were observed among groups. CONCLUSIONS Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.
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Affiliation(s)
- Brian G Feagan
- Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois
| | | | | | | | - Serap Sankoh
- Takeda Pharmaceuticals International Co, Cambridge, Massachusetts
| | - Alexandra James
- Takeda Development Centre Europe Ltd, London, United Kingdom
| | - Michael Smyth
- Takeda Development Centre Europe Ltd, London, United Kingdom
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Harzallah I, Rigaill J, Williet N, Paul S, Roblin X. Golimumab pharmacokinetics in ulcerative colitis: a literature review. Therap Adv Gastroenterol 2017; 10:89-100. [PMID: 28286562 PMCID: PMC5330616 DOI: 10.1177/1756283x16676194] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM's exposure-response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient's improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM.
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Affiliation(s)
- Ines Harzallah
- Laboratoire d’Immunologie et d’Immunomonitoring, CIC1408, GIMAPEA3064, CHU de Saint-Etienne, France
| | - Josselin Rigaill
- Laboratoire d’Immunologie et d’Immunomonitoring, CIC1408, GIMAPEA3064, CHU de Saint-Etienne, France
| | - Nicolas Williet
- Department of Gastroenterology, Service de Gastrologie-Enterologie-Hepatologie, CHU de Saint-Etienne, France
| | - Stephane Paul
- Laboratoire d’Immunologie et d’Immunomonitoring, CIC1408, GIMAPEA3064, CHU de Saint-Etienne, France
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Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis 2017; 23:97-106. [PMID: 27930408 DOI: 10.1097/mib.0000000000000979] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations. CONCLUSIONS Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.
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Comparable outcomes of the consistent use versus switched use of anti- tumor necrosis factor agents in postoperative recurrent Crohn's disease following ileocolonic resection. Int J Colorectal Dis 2016; 31:1751-1758. [PMID: 27475090 DOI: 10.1007/s00384-016-2632-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE There are no published data or guidelines on whether the same anti-tumor-necrosis factor (TNF) agents used preoperatively or different anti-TNF agents are preferable to treat postoperative recurrence. Our aim was to compare the efficacy of the consistent vs. switched anti-TNF approaches in patients with recurrent Crohn's disease (CD) after their inception ileocolonic resection (ICR). METHODS Patients with CD receiving anti-TNF agents before the inception ICR who were treated for clinical recurrence with the same or different anti-TNF agents after surgical resection were included in the study. The outcome of the study was the need for the subsequent resection of ileocolonic anastomosis (ICA) as calculated with survival curves. RESULTS Eighty-five patients were included in the study. The mean age of the whole cohort at the inception ICR was 35.1 ± 13.5 years. The whole cohort consisted 42 (49.4 %) in the consistent group and 43 (50.6 %) in the switched group. No significant differences were observed in demographic and clinical variables between the two groups. During the median follow-up of 1.5 (interquartile range, 0.8-3.1) years, seven (16.7 %) patients in the consistent group and eight (18.6 %) in the switched group required the repeat resection of ICA. Similar results were found in terms of the subsequent resection of ICA-free survival (hazard ratio = 1.36, 95 % confidence interval 0.49-3.76, P = 0.54) between the consistent and switched groups. CONCLUSIONS The adherence to the same anti-TNF agent appeared to be as effective as the switching approach to different anti-TNF agent in treating postoperative recurrent CD after the inception ICR.
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Marini JC, Sendecki J, Cornillie F, Popp JW, Black S, Blank M, Gils A, Van Stappen T, Hamann D, Rispens T, Thérien L, Chun K, Shankar G. Comparisons of Serum Infliximab and Antibodies-to-Infliximab Tests Used in Inflammatory Bowel Disease Clinical Trials of Remicade®. AAPS JOURNAL 2016; 19:161-171. [PMID: 27600137 DOI: 10.1208/s12248-016-9981-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 08/25/2016] [Indexed: 02/08/2023]
Abstract
Monitoring infliximab (IFX) concentrations and antibodies-to-IFX (ATI) titers during inflammatory bowel disease treatment may allow more informed decisions in assessing exposure/response and determining appropriate dosing. To aid in interpreting results from different commercial tests in the context of Janssen's published Remicade® results, the reliability of Janssen's IFX and ATI assays was compared with commercial assays from KU Leuven, Sanquin, Dynacare, and LabCorp. Test results were independently reported to Janssen. All assays were tested for specificity, selectivity, and precision. ATI assays were evaluated for sensitivity, drug interference, and potential interference of tumor necrosis factor-alpha (TNF-α). IFX assays were specific, accurate, and reproducible. Intra-class correlation of Janssen IFX assay results with those from KU Leuven, Sanquin, Dynacare, and LabCorp were 0.960, 0.895, 0.931, and 0.971, respectively. ATI titers >10 interfered with IFX assessment in all IFX assays, whereas TNF-α (≤50 ng/mL) did not interfere with IFX detection in any assay. ATI assays specifically and reproducibly detected ATI. Janssen, Sanquin, and LabCorp ATI methods were more resistant to IFX interference than Dynacare and KU Leuven, which were affected by IFX concentrations at ≥2 μg/mL. TNF-α (<5 ng/mL) did not interfere with ATI detection. Strong agreement was observed between Janssen's IFX and ATI assays and the diagnostic service provider assays. Our study results indicate that all four commercially available assays are suitable for therapeutic drug monitoring of IFX. The substantial agreement reported here between the comparator assays and the Janssen drug-tolerant assay provides support to clinicians in their use of these commercial assays, and for understanding their patients' IFX and ATI results relative to published data from clinical studies of Remicade.
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Affiliation(s)
- Joseph C Marini
- Biologics Development Sciences, Janssen Research & Development, LLC, Spring House, PA, USA
| | - Jocelyn Sendecki
- Nonclinical Statistics, Janssen Research & Development, LLC, Spring House, PA, USA
| | - Freddy Cornillie
- Janssen Biologics BV, Leiden, The Netherlands.,Medical Affairs, Immunology, MSD International, Kriens, Switzerland
| | - John W Popp
- Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Shawn Black
- Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Marion Blank
- Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Ann Gils
- Department of Pharmaceutical Sciences, KU Leuven, Leuven, Belgium
| | | | - Dörte Hamann
- Sanquin Diagnostic Services, Amsterdam, The Netherlands
| | - Theo Rispens
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands
| | | | | | - Gopi Shankar
- Biologics Development Sciences, Janssen Research & Development, LLC, Spring House, PA, USA.
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Comparison of Three Assays to Quantify Infliximab, Adalimumab, and Etanercept Serum Concentrations. Ther Drug Monit 2016; 38:432-8. [DOI: 10.1097/ftd.0000000000000310] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies. Inflamm Bowel Dis 2016; 22:1999-2015. [PMID: 27135483 DOI: 10.1097/mib.0000000000000772] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention. METHODS Literature review. RESULTS Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques. CONCLUSIONS TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.
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Baert F, Kondragunta V, Lockton S, Vande Casteele N, Hauenstein S, Singh S, Karmiris K, Ferrante M, Gils A, Vermeire S. Antibodies to adalimumab are associated with future inflammation in Crohn's patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial. Gut 2016; 65:1126-31. [PMID: 25862647 DOI: 10.1136/gutjnl-2014-307882] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 03/21/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Data on immunogenicity to adalimumab (ADL) therapy in patients with IBD is limited. We performed additional analyses on the Karmiris cohort using the homogeneous mobility shift assay (HMSA) focusing on the inter-relationship of serum ADL concentration, antibodies-to-adalimumab (ATA), inflammatory markers and sustained response. METHODS 536 prospectively collected serum samples were available for analysis of ADL concentration and ATA using HMSA. We studied the role of week 4 serum ADL concentration and immunomodulator (IMM) use on ATA formation with a Cox proportional hazards model. Mixed model repeated measures analysis was performed to assess the independent effects of serum ADL concentration and ATA on C-reactive protein (CRP) and response. RESULTS ATA was detected in 20% of patients after a median of 34 (12.4-60.5) weeks. ATA-positive samples correlated with lower serum ADL concentration (p<0.001). Cox regression modelling showed that week 4 ADL concentration of <5 µg/mL significantly increased the future risk of ATA formation (HR=25.1; 95% CI 5.6 to 111.9; p=0.0002) and that IMM co-treatment prevented ATA formation (HR=0.23; 95% CI 0.06 to 0.86; p=0.0293). Regression modelling showed a negative correlation between CRP and ADL concentration (p=0.0001) and a positive one with ATA (p=0.0186). The model revealed that both lower serum ADL concentration and ATA were independently associated with future CRP (p=0.0213 and p=0.0013 respectively). ATA positivity was associated with discontinuation of ADL because of loss or response (OR=3.04; 95% CI 1.039 to 9.093; p=0.034). CONCLUSIONS ATA were detected in 20% of patients. Risk of ATA formation increased with lower early serum ADL concentration and in patients not on IMM. ATA and ADL were strongly associated with higher future CRP level and discontinuation of ADL.
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Affiliation(s)
- Filip Baert
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Niels Vande Casteele
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | | | - Sharat Singh
- Prometheus Laboratories, San Diego, California, USA
| | - Konstantinos Karmiris
- Department of Gastroenterology, Venizeleio General Hospital, Heraklion Crete, Greece
| | - Marc Ferrante
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
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Ben-Horin S, Yavzori M, Benhar I, Fudim E, Picard O, Ungar B, Lee S, Kim S, Eliakim R, Chowers Y. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut 2016; 65:1132-8. [PMID: 25897019 DOI: 10.1136/gutjnl-2015-309290] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 03/28/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The cross-immunogenicity of the recently approved infliximab-biosimilar Remsima (CT-P13) with the originator drug Remicade is still unknown. DESIGN Sera of patients with IBD with or without measurable anti-Remicade antibodies to infliximab (ATI) were tested for their cross-reactivity to two batches of Remsima. Experiments were repeated after deglycosylation of Remicade/Remsima, IgG purification, excipients' dialysis and monomer purification by size exclusion chromatography. Anti-Remicade antibodies were tested for their functional inhibition of TNF-α binding by Remsima/Remicade by competition assay. Cross-reactivity of anti-adalimumab antibodies with Remicade/Remsima was also investigated. RESULTS 125 patients' and controls' sera were tested (median age 31 years, IQR 24.5-39.5). All 56 anti-Remicade ATI-negative controls (14 healthy individuals, 42 patients with IBD) were also negative for anti-Remsima ATI. All 69 positive anti-Remicade IBD sera were cross-reactive with Remsima. ATI titres against Remicade or Remsima were strongly correlated (r values between 0.92 and 0.99, p<0.001 for all experiments, Spearman's correlation test). The background ELISA signal for Remsima was slightly higher compared with Remicade in negative controls (1.25±0.6 µg/mL vs 0.76±0.5 µg/mL, respectively, p<0.001), and persisted after deglycosylation, dialysis or protein size filtration, but abolished by IgG purification and significantly diminished by monomer purification. Anti-Remicade ATIs of patients with IBD (n=10) exerted similar functional inhibition on Remsima or Remicade TNF-α binding capacity (p=NS for all inhibition curve points). Antibodies-to-adalimumab in adalimumab-treated patients with IBD (n=7) did not cross-react with either Remicade or Remsima. CONCLUSIONS Anti-Remicade antibodies in patients with IBD recognise and functionally inhibit Remsima to a similar degree, suggesting similar immunogenicity and shared immunodominant epitopes on these two infliximab agents. In contrast, anti-adalimumab antibodies do not cross-react with Remsima or Remicade.
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Affiliation(s)
- Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Miri Yavzori
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Itai Benhar
- Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel
| | - Ella Fudim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Orit Picard
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Bella Ungar
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | | | | | - Rami Eliakim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Yehuda Chowers
- Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel
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Crommelin HA, van der Burg LM, Vorselaars ADM, Drent M, van Moorsel CHM, Rijkers GT, Deneer VHM, Grutters JC. Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. Respir Med 2016; 115:72-7. [PMID: 27215507 DOI: 10.1016/j.rmed.2016.04.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 04/08/2016] [Accepted: 04/21/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-α) inhibitors are regarded as the third-line therapy in sarcoidosis, the first choice generally being infliximab. To date, data regarding response to adalimumab in sarcoidosis patients intolerant to infliximab are lacking. The objective of this retrospective observational study was to establish if adalimumab could achieve stabilization or improvement of the disease in refractory sarcoidosis patients who developed intolerance to infliximab. MATERIAL AND METHODS Sarcoidosis patients referred to St Antonius Interstitial Lung Diseases Center of Excellence, Nieuwegein, The Netherlands, between January 2008 and April 2015 who switched from infliximab to adalimumab were included. Changes in organ function, inflammatory biomarker levels, and adverse events were retrieved from medical records. RESULTS Out of 142 infliximab treated patients, 18 (13%) had to discontinue treatment due to antibody formation or severe adverse events and switched to adalimumab therapy. Organ function improved in 7 patients (39%), was stable in 6 patients (33%), and worsened in 5 patients (28%) after 12 months of treatment or after 6 months if evaluation after 12 months was not available (n = 4). In none of the patients biomarker levels of soluble interleukin-2 receptor (sIL-2R) deteriorated. Median decrease in sIL-2R was 3614 pg/mL. Most reported adverse event was infection (n = 10). CONCLUSIONS Adalimumab is an effective alternative for patients intolerant to infliximab. The switch to adalimumab achieved clinical improvement in 39% and stabilization in 33% of patients intolerant to infliximab. Further research is needed to develop guidelines on how to use adalimumab for sarcoidosis in terms of dosing regimen.
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Affiliation(s)
- Heleen A Crommelin
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Leone M van der Burg
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Science Department, University College Roosevelt, Middelburg, The Netherlands
| | - Adriane D M Vorselaars
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Marjolein Drent
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands
| | - Coline H M van Moorsel
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands
| | - Ger T Rijkers
- Science Department, University College Roosevelt, Middelburg, The Netherlands; Department of Medical Microbiology and Immunology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Vera H M Deneer
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.
| | - Jan C Grutters
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands
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López-Ibáñez M, Marín-Jiménez I. Niveles de fármaco y anticuerpos antifármaco en el manejo clínico del paciente con enfermedad inflamatoria intestinal. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:265-72. [DOI: 10.1016/j.gastrohep.2015.09.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 06/25/2015] [Accepted: 09/15/2015] [Indexed: 02/08/2023]
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49
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Bendtzen K, Steenholdt C, Brynskov J, Thomsen OØ, Ainsworth MA. Monitoring immunogenicity of protein-based TNF antagonists. Frontline Gastroenterol 2016; 7:152-154. [PMID: 28839850 PMCID: PMC5369473 DOI: 10.1136/flgastro-2015-100596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 04/29/2015] [Indexed: 02/04/2023] Open
Affiliation(s)
- Klaus Bendtzen
- Institute for Inflammation Research, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Casper Steenholdt
- Department of Gastroenterology, Herlev Hospital, Copenhagen, Denmark
| | - Jørn Brynskov
- Department of Gastroenterology, Herlev Hospital, Copenhagen, Denmark
| | - Ole Ø Thomsen
- Department of Gastroenterology, Herlev Hospital, Copenhagen, Denmark
| | - Mark A Ainsworth
- Department of Gastroenterology, Herlev Hospital, Copenhagen, Denmark
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50
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Ungar B, Levy I, Yavne Y, Yavzori M, Picard O, Fudim E, Loebstein R, Chowers Y, Eliakim R, Kopylov U, Ben-Horin S. Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2016; 14:550-557.e2. [PMID: 26538204 DOI: 10.1016/j.cgh.2015.10.025] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/02/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein. RESULTS Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 μg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 μg/mL, P = .01). Levels of infliximab above 5 μg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 μg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 μg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 μg/mL. In patients with measurable levels of infliximab >3 μg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003). CONCLUSIONS In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.
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Affiliation(s)
- Bella Ungar
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Idan Levy
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yarden Yavne
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Miri Yavzori
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orit Picard
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ella Fudim
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ronen Loebstein
- Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yehuda Chowers
- Israel Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Rami Eliakim
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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