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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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Srinivasan A, van Langenberg D, De Cruz P, Segal J, Vasudevan A, Upton RN. Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study. BioDrugs 2024; 38:691-702. [PMID: 39168947 PMCID: PMC11358351 DOI: 10.1007/s40259-024-00673-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. OBJECTIVES This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. METHODS A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn's disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn's disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively. RESULTS The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p < 0.01). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest infliximab trough levels (all p < 0.01). CONCLUSION This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.
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Affiliation(s)
- Ashish Srinivasan
- Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.
- Monash University, Eastern Health Clinical School, Melbourne, VIC, Australia.
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia.
- The University of Melbourne, Austin Academic Centre, Melbourne, VIC, Australia.
| | | | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia
- The University of Melbourne, Austin Academic Centre, Melbourne, VIC, Australia
| | - Jonathan Segal
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia
- Monash University, Eastern Health Clinical School, Melbourne, VIC, Australia
| | - Richard N Upton
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
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Rodríguez-Moranta F, Argüelles-Arias F, Hinojosa Del Val J, Iborra Colomino M, Martín-Arranz MD, Menchén Viso L, Muñoz Núñez F, Ricart Gómez E, Sánchez-Hernández JG, Valdés-Delgado T, Guardiola Capón J, Barreiro-de Acosta M, Mañosa Ciria M, Zabana Abdo Y, Gutiérrez Casbas A. Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:522-552. [PMID: 38311005 DOI: 10.1016/j.gastrohep.2024.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/31/2023] [Accepted: 01/18/2024] [Indexed: 02/06/2024]
Abstract
The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.
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Affiliation(s)
- Francisco Rodríguez-Moranta
- Servicio de Aparato Digestivo, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España.
| | - Federico Argüelles-Arias
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España; Facultad de Medicina, Universidad de Sevilla, Sevilla, España
| | | | - Marisa Iborra Colomino
- Servicio de Aparato Digestivo, Hospital Universitario y Politécnico de La Fe, Valencia, España
| | - M Dolores Martín-Arranz
- Servicio de Aparato Digestivo, Hospital Universitario La Paz, Facultad de Medicina de la UAM, Fundación para la investigación del Hospital Universitario la Paz (IDIPAZ), Madrid, España
| | - Luis Menchén Viso
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón-IiSGM, Madrid, España; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
| | - Fernando Muñoz Núñez
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, España
| | - Elena Ricart Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), H. Clínic Barcelona, Barcelona, IDIBAPS, Barcelona, España
| | | | - Teresa Valdés-Delgado
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España
| | - Jordi Guardiola Capón
- Servicio de Gastroenterología, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España
| | - Manuel Barreiro-de Acosta
- Servicio de Gastroenterología, Hospital Clínico Universitario de Santiago, A Coruña, España; Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), A Coruña, España
| | - Míriam Mañosa Ciria
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España
| | - Yamile Zabana Abdo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Mútua de Terrassa (HMT), Terrassa, Barcelona, España
| | - Ana Gutiérrez Casbas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, España
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Gisbert JP, Chaparro M. De-escalation of Biologic Treatment in Inflammatory Bowel Disease: A Comprehensive Review. J Crohns Colitis 2024; 18:642-658. [PMID: 37943286 DOI: 10.1093/ecco-jcc/jjad181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Indexed: 11/10/2023]
Abstract
INTRODUCTION Biologic therapy is an effective treatment for inflammatory bowel disease [IBD]. However due to cost and safety concerns, dose de-escalation strategies after achieving remission have been suggested. AIM To critically review available data on dose de-escalation of biologics [or other advanced therapies] in IBD. We will focus on studies evaluating de-escalation to standard dosing in patients initially optimised, and also on studies assessing de-escalation from standard dosing. METHODS A systematic bibliographic search was performed. RESULTS The mean frequency of de-escalation after previous dose intensification [12 studies, 1,474 patients] was 34%. The corresponding frequency of de-escalation from standard dosing [five studies, 3,842 patients] was 4.2%. The relapse rate of IBD following anti-tumour necrosis factor [TNF] de-escalation to standard dosing in patients initially dose-escalated [10 studies, 301 patients] was 30%. The corresponding relapse rate following anti-TNF de-escalation from standard dosing [nine studies, 494 patients] was 38%. The risk of relapse was lower for patients in clinical, biologic, and endoscopic/radiological remission at the time of de-escalation. A role of anti-TNF therapeutic drug monitoring in the decision to dose de-escalate has been demonstrated. In patients relapsing after de-escalation, re-escalation is generally effective. De-escalation is not consistently associated with a better safety profile. The cost-effectiveness of the de-escalation strategy remains uncertain. Finally, there is not enough evidence to recommend dose de-escalation of biologics different from anti-TNFs or small molecules. CONCLUSIONS Any consideration for de-escalation of biologic therapy in IBD must be tailored, taking into account the risks and consequences of a flare and patients' preferences.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, 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], Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, 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], Madrid, Spain
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Shah NB, Zuckerman AD, Hosteng KR, Fann J, DeClercq J, Choi L, Cherry L, Schwartz DA, Horst S. Insurance Approval Delay of Biologic Therapy Dose Escalation Associated with Disease Activity in Patients with Inflammatory Bowel Disease. Dig Dis Sci 2023; 68:4331-4338. [PMID: 37725192 DOI: 10.1007/s10620-023-08098-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 08/26/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Dose escalation of self-injectable biologic therapy for inflammatory bowel diseases may be required to counteract loss of response and/or low drug levels. Payors often require completion of a prior authorization (PA), which is a complex approval pathway before providing coverage. If the initial PA request is denied, clinic staff must complete a time and resource-intensive process to obtain medication approval. AIMS This study measured time from decision to dose escalate to insurance approval and evaluated impact of approval time on disease activity. METHODS This was a single-center retrospective analysis of adult patients with IBD prescribed an escalated dose of biologic therapy at an academic center with an integrated specialty pharmacy team from January to December 2018. Outcomes included time to insurance approval and the association between approval time and follow-up C-reactive protein (CRP) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores. Associations were tested using linear regression analyses. RESULTS 220 patients were included, median age 39, 53% female, and 96% white. Overall median time from decision to dose escalate to insurance approval was 7 days [interquartile range (IQR) 1, 14]. Approval time was delayed when an appeal was required [median of 29 days (IQR 17, 43)]. Patients with a longer time to insurance approval were less likely to have CRP improvement (p = 0.019). Time to insurance approval did not significantly impact follow-up SIBDQ scores. CONCLUSION Patients who had a longer time to insurance approval were less likely to have improvement in CRP, highlighting the negative clinical impact of a complex dose escalation process.
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Affiliation(s)
- Nisha B Shah
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Autumn D Zuckerman
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA.
| | - Katie R Hosteng
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Jessica Fann
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Josh DeClercq
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Leena Choi
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Laura Cherry
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - David A Schwartz
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
| | - Sara Horst
- Vanderbilt University Medical Center, 784 Melrose Avenue, Nashville, TN, 37211, USA
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Wang LF, Chen PR, He SK, Duan SH, Zhang Y. Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review. World J Gastroenterol 2023; 29:4481-4498. [PMID: 37621757 PMCID: PMC10445007 DOI: 10.3748/wjg.v29.i29.4481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.
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Affiliation(s)
- Liang-Fang Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ping-Run Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Ke He
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Hao Duan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
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Panaccione R, Lee WJ, Clark R, Kligys K, Campden RI, Grieve S, Raine T. Dose Escalation Patterns of Advanced Therapies in Crohn's Disease and Ulcerative Colitis: A Systematic Literature Review. Adv Ther 2023; 40:2051-2081. [PMID: 36930430 PMCID: PMC10129944 DOI: 10.1007/s12325-023-02457-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/10/2023] [Indexed: 03/18/2023]
Abstract
INTRODUCTION Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC. METHODS Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]). RESULTS Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks. CONCLUSION Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation. PROSPERO REGISTRATION CRD42021289251.
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Affiliation(s)
- Remo Panaccione
- Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Unit, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | | | | | | | | | | | - Tim Raine
- Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Crispino F, Michielan A, Grova M, Tieppo C, Mazza M, Rogger TM, Armelao F. Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors. World J Clin Cases 2023; 11:2657-2669. [PMID: 37214561 PMCID: PMC10198103 DOI: 10.12998/wjcc.v11.i12.2657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/10/2023] [Accepted: 03/29/2023] [Indexed: 04/25/2023] Open
Abstract
The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4β7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.
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Affiliation(s)
- Federica Crispino
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Andrea Michielan
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Mauro Grova
- Inflammatory Bowel Disease Unit, Department of Medicine, Azienda Ospedaliera Ospedali Riuniti, Villa Sofia-Cervello, Palermo 90146, Italy
| | - Chiara Tieppo
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Marta Mazza
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Teresa Marzia Rogger
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Franco Armelao
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
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Srinivasan A, De Cruz P, Sam M, Toong C, van Langenberg DR. Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses. J Gastroenterol Hepatol 2023; 38:724-732. [PMID: 36692034 DOI: 10.1111/jgh.16133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. METHODS A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5 mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5 mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. RESULTS Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02 ug/mL, P = 0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P > 0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36 ug/mL, P < 0.01), 12 (8.94 vs 5.96 ug/mL, P = 0.02) and 30 (3.89 vs 6.35 ug/mL, P = .0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P = 0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P = 0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P = 0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P = 0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6 ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P < 0.05) predicted nonresponse at week 32. CONCLUSION Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.
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Affiliation(s)
- Ashish Srinivasan
- Department of Gastroenterology, Eastern Health, Melbourne, Australia.,Eastern Health Clinical School, Monash University, Melbourne, Australia.,Department of Gastroenterology, Austin Health, Melbourne, Australia.,Austin Academic Centre, University of Melbourne, Melbourne, Australia
| | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, Australia.,Austin Academic Centre, University of Melbourne, Melbourne, Australia
| | - Melissa Sam
- Department of Immunopathology, NSW Health Pathology Liverpool Hospital, Sydney, Australia.,Ingham Institute of Applied Sciences, Immunology Research Group, Sydney, Australia.,South Western Sydney Clinical School, University of NSW, Sydney, Australia
| | - Catherine Toong
- Department of Immunopathology, NSW Health Pathology Liverpool Hospital, Sydney, Australia.,Ingham Institute of Applied Sciences, Immunology Research Group, Sydney, Australia.,South Western Sydney Clinical School, University of NSW, Sydney, Australia.,Department of Immunology, Liverpool Hospital, Sydney, Australia
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10
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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11
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Patel D, Martin S, Luo M, Ursos L, Lirio RA, Kamble P, Wang S. Real-World Effectiveness of Vedolizumab Dose Escalation in Patients With Inflammatory Bowel Disease: A Systematic Literature Review. CROHN'S & COLITIS 360 2022; 4:otac020. [PMID: 36777427 PMCID: PMC9802433 DOI: 10.1093/crocol/otac020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background Vedolizumab is a gut-selective anti-lymphocyte trafficking agent approved for the treatment of moderate to severely active inflammatory bowel disease (IBD: ulcerative colitis [UC] and Crohn's disease [CD]). Methods A systematic literature review (SLR) of real-world studies was conducted to assess the effectiveness of dose escalation of vedolizumab every 8 weeks (Q8W) during maintenance treatment to achieve a response in patients who were either vedolizumab responders experiencing secondary loss of response (SLOR) or non-responders. MEDLINE and EMBASE databases were searched from January 2014 to August 2021. Results Screening of SLR outputs identified 72 relevant real-world study publications featuring dose escalation of vedolizumab maintenance therapy. After qualitative review, ten eligible studies (9 articles, 1 abstract) were identified as reporting clinical response and/or clinical remission rates following escalation of intravenous vedolizumab 300 mg Q8W maintenance dosing to every 4 weeks (Q4W) maintenance dosing in adult patients with UC/CD (≥10 patients per study). Overall, 196/395 (49.6%) patients with IBD had a response within 54 weeks of vedolizumab maintenance dose escalation. Although definitions for clinical response/remission varied across the 10 studies, clinical response rates after escalated vedolizumab Q8W maintenance dosing ranged from 40.0% to 73.3% (9 studies) and from 30.0% to 55.8% for remission (4 studies) over a range of 8 to <58 weeks' follow-up. Conclusions This synthesis of real-world effectiveness data in vedolizumab-treated patients with IBD indicates that approximately half were able to achieve or recapture clinical response after escalating vedolizumab maintenance dosing.
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Affiliation(s)
| | | | | | - Lyann Ursos
- Takeda Pharmaceuticals USA Inc., Deerfield, Illinois, USA
| | | | | | - Song Wang
- Takeda, Cambridge, Massachusetts, USA
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12
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Roblin X, Genin C, Nancey S, Williet N, Veyrard P, Boschetti G, Phelip JM, Berger AE, Killian M, Waeckel L, Flourie B, Paul S. Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels. Inflamm Bowel Dis 2022; 28:720-727. [PMID: 34405867 DOI: 10.1093/ibd/izab158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. METHODS Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. RESULTS Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. CONCLUSION In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.
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Affiliation(s)
- Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Capucine Genin
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Stéphane Nancey
- Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1 and INSERM U1111, Lyon, France
| | - Nicolas Williet
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Pauline Veyrard
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Gilles Boschetti
- Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1 and INSERM U1111, Lyon, France
| | - Jean-Marc Phelip
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Anne-Emmanuelle Berger
- Department of Immunology, CIC1408, GIMAP U1111/UMR5308 INSERM-UJM-UCBL-ENS de Lyon-CNRS, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Martin Killian
- Department of Internal Medicine, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Louis Waeckel
- Department of Immunology, CIC1408, GIMAP U1111/UMR5308 INSERM-UJM-UCBL-ENS de Lyon-CNRS, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Bernard Flourie
- Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1 and INSERM U1111, Lyon, France
| | - Stéphane Paul
- Department of Immunology, CIC1408, GIMAP U1111/UMR5308 INSERM-UJM-UCBL-ENS de Lyon-CNRS, University Hospital of Saint-Etienne, Saint-Etienne, France
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13
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Abstract
BACKGROUND Limited data are available on biological therapy de-escalation after prior escalation in inflammatory bowel disease (IBD) patients. This study aimed to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and to evaluate which measures are used to guide de-escalation. METHODS This multicentre retrospective cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated after prior biological escalation. De-escalations were considered pharmacokinetic-driven if based on clinical symptoms combined with therapeutic or supratherapeutic trough levels, and disease activity-driven if based on faecal calprotectin less than or equal to 200 µg/g or resolution of perianal fistula drainage or closure or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for greater than or equal to 6 months after de-escalation without the need for corticosteroids. RESULTS In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these patients, 34 (17%) on IFX, 18 (21%) on ADA and 8 (15%) on VEDO underwent therapy de-escalation. De-escalation was successful in 88% of IFX patients, 89% of ADA and 100% of VEDO. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. Disease activity-driven de-escalations were more often successful (97%) than pharmacokinetic- and no marker-driven de-escalations (76%); P = 0.017. CONCLUSION De-escalation after biological dose escalation was successful in the majority of carefully selected IBD patients. Objective assessment of remission increased the likelihood of successful de-escalation.
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14
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Srinivasan A, Gilmore R, van Langenberg D, De Cruz P. Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn's disease. Therap Adv Gastroenterol 2022; 15:17562848211070940. [PMID: 35126667 PMCID: PMC8814980 DOI: 10.1177/17562848211070940] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/15/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Anti-tumor necrosis factor (TNF) dose intensification represents an effective method of overcoming secondary loss of response (LOR); however, a subset of patients may not respond (tertiary non-response), or fail to demonstrate durable response (tertiary LOR) to intensified dosing. This systematic review and meta-analysis aimed to evaluate these outcomes to determine the clinical effectiveness of empiric dose intensification in Crohn's disease. METHODS Multiple databases including MEDLINE and EMBASE were interrogated to identify studies that reported outcomes following anti-TNF dose intensification to address secondary LOR in Crohn's disease. Studies that used anti-TNF levels as the primary basis for dose intensification were excluded. Studies that reported (1) tertiary response and tertiary non-response within 6 months or (2) tertiary response and tertiary LOR beyond 6 months, were pooled using a random effects model with risk ratio (RR) derived, quantifying the effect of each comparison. RESULTS Twenty-six studies reported outcomes following anti-TNF dose intensification to address secondary LOR. Short-term response within 12 weeks of any dose-intensification strategy was 33-90%, while sustained response (⩾48 weeks) was achieved in 25-85%. Tertiary non-response occurred in up to 45% of intensified patients within 6 months of anti-TNF dose intensification, while tertiary LOR beyond 6 months occurred in up to 64% of patients. Tertiary response was more likely than tertiary non-response within 6 months (RR 2.58, 95% CI (1.76, 3.79), I 2 = 82%, 12 studies), while sustained response beyond 6 months compared to tertiary LOR (RR 1.10 (0.75, 1.61) I 2 = 85%, 7 studies) was less convincing. CONCLUSION Although anti-TNF dose intensification is clinically effective in patients with Crohn's disease, particularly within the first 6 months, a proportion of patients will fail to demonstrate short-term and/or sustained clinical response. Hence, clinical reassessment following anti-TNF dose intensification, particularly beyond 6 months, remains important to differentiate between effective and ineffective dose-intensification strategies.
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Affiliation(s)
| | - Robert Gilmore
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia
| | - Daniel van Langenberg
- Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia,Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia,Department of Medicine, Melbourne University, Melbourne, VIC, Australia
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15
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Soo WT, Costello SP, Bryant RV. Dialing Back M for Monoclonal: Successful De-escalation of Dose-Intensified Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Dig Dis Sci 2022; 67:8-10. [PMID: 33763788 DOI: 10.1007/s10620-021-06946-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2021] [Indexed: 12/09/2022]
Affiliation(s)
- Wei Ting Soo
- IBD Service, Department of Gastroenterology, The Queen Elizabeth Hospital, 28 Woodville Rd,, Woodville South, SA, 5011, Australia
- School of Medicine, Faculty of Health Sciences, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia
| | - Samuel P Costello
- IBD Service, Department of Gastroenterology, The Queen Elizabeth Hospital, 28 Woodville Rd,, Woodville South, SA, 5011, Australia
- School of Medicine, Faculty of Health Sciences, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia
| | - Robert V Bryant
- IBD Service, Department of Gastroenterology, The Queen Elizabeth Hospital, 28 Woodville Rd,, Woodville South, SA, 5011, Australia.
- School of Medicine, Faculty of Health Sciences, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia.
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16
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Little RD, Chu IE, Ward MG, Sparrow MP. De-escalation from Dose-Intensified Anti-TNF Therapy Is Successful in the Majority of IBD Patients at 12 Months. Dig Dis Sci 2022; 67:259-262. [PMID: 33763785 DOI: 10.1007/s10620-021-06937-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/16/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate. AIMS To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. METHODS Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly. RESULTS Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation. CONCLUSION Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.
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Affiliation(s)
- Robert D Little
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, 3004, Australia
| | - Isabel E Chu
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, 3004, Australia
| | - Mark G Ward
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, 3004, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, 3004, Australia.
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17
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Annese V, Nathwani R, Alkhatry M, Al-Rifai A, Al Awadhi S, Georgopoulos F, Jazzar AN, Khassouan AM, Koutoubi Z, Taha MS, Limdi JK. Optimizing biologic therapy in inflammatory bowel disease: a Delphi consensus in the United Arab Emirates. Therap Adv Gastroenterol 2021; 14:17562848211065329. [PMID: 34987611 PMCID: PMC8721421 DOI: 10.1177/17562848211065329] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic, relapsing-remitting inflammatory conditions with a substantial negative impact on health-related quality of life and work productivity. Treatment of IBD has been revolutionized by the advent of biologic therapies, initially with anti-TNF agents and more recently with multiple alternatives targets, and yet more under development. OBJECTIVES Approximatively one third of patients do not respond to biologic therapy and more importantly a significant proportion experiences partial response or loss of response during treatment. The latter are common clinical situations and paradoxically are not addressed in the commercial drug labels and available guidelines. There is therefore a clinical need for physicians to understand when and how eventually to optimize the biologic therapy. DESIGN This consensus using a Delphi methodology was promoted and supported by the Emirates Society of Gastroenterology and Hepatology to close this gap. DATA SOURCES AND METHODS Following an extensive systematic review of over 60,000 studies, 81 studies with dose escalation and five addressing drug monitoring were selected and in addition five systematic reviews and three guidelines. RESULTS AND CONCLUSION after three rounds of voting 18 statements were selected with agreement ranging from of 80% to 100.
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Affiliation(s)
- Vito Annese
- Department of Gastroenterology, Fakeeh University Hospital, Dubai, United Arab Emirates
| | - Rahul Nathwani
- Department of Gastroenterology, Mediclinic City Hospital, Mohammed Bin Rashid University, Dubai, United Arab Emirates
| | - Maryam Alkhatry
- Gastroenterology and Endoscopy Department, Ibrahim Bin Hamad Obaid Allah Hospital, Ministry of Health and Prevention, Ras Al Khaimah, United Arab Emirates
| | - Ahmad Al-Rifai
- Department of Gastroenterology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Sameer Al Awadhi
- Digestive Disease Unit, Rashid Hospital, Dubai, United Arab Emirates
| | - Filippos Georgopoulos
- Gastroenterology and Endoscopy Unit, Al Zahra Hospital Dubai, Dubai, United Arab Emirates
| | - Ahmad N. Jazzar
- Gastroenterology Division, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | | | - Zaher Koutoubi
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Mazen S. Taha
- Gastroenterology and Hepatology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Jimmy K. Limdi
- Department of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester Academic Health Sciences, University of Manchester, Manchester, UK
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18
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Narula N, Wong ECL, AlRamdan R, Bualbanat H, Marshall JK, Steinhart AH, Greener T, Silverberg MS. Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis. J Gastroenterol Hepatol 2021; 36:2803-2812. [PMID: 34020510 DOI: 10.1111/jgh.15551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. METHODS In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40 mg subcutaneous (sc) weekly or 80 mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40 mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. RESULTS Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6 years (interquartile range [IQR] 4.0-9.6) and 3.0 years (IQR 0.9-9.4) in the SD group (log-rank test P = 0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P = 0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P = 1.0). Results were similar in the propensity score-matched cohort. CONCLUSIONS High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.
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Affiliation(s)
- Neeraj Narula
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Emily C L Wong
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Raed AlRamdan
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Hasan Bualbanat
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - John K Marshall
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - A Hillary Steinhart
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Toronto, Ontario, Canada.,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Tomer Greener
- Edit Wolfson Medical Center, Tel-Aviv University, Tel-Aviv, Israel
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Toronto, Ontario, Canada.,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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19
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Visuri I, Eriksson C, Olén O, Cao Y, Mårdberg E, Grip O, Gustavsson A, Hjortswang H, Karling P, Montgomery S, Myrelid P, Ludvigsson JF, Halfvarson J. Predictors of drug survival: A cohort study comparing anti-tumour necrosis factor agents using the Swedish inflammatory bowel disease quality register. Aliment Pharmacol Ther 2021; 54:931-943. [PMID: 34286871 DOI: 10.1111/apt.16525] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/25/2021] [Accepted: 06/26/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Whether long-term effectiveness differs between anti-tumour necrosis factor (anti-TNF) agents is unknown. AIMS To examine drug survival of first-line anti-TNF agents and identify predictors of discontinuation. To reduce channelling bias, we also compared drug survival of the second anti-TNF. METHODS Biologic-naïve patients (N = 955) recorded in the Swedish IBD Quality Register (SWIBREG) were examined. We used propensity score matching, comparing drug survival over up to three years of follow-up. Cox regression estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). RESULTS In Crohn's disease, discontinuation because of lack/loss of response was 32% [95%CI = 26%-38%] for infliximab versus 16% [95%CI = 11%-21%] for adalimumab. Infliximab [vs adalimumab; aHR = 1.96; 95%CI = 1.20-3.21] and colonic disease (L2) [vs no L2; aHR = 2.17; 95% CI = 1.26-3.75] were associated with higher discontinuation rates, whereas normalised CRP at three months [aHR = 0.40; 95% CI = 0.19-0.81] with a lower rate. Consistently, patients who switched from adalimumab to infliximab (vs infliximab to adalimumab) had earlier discontinuation (P = 0.04). Concomitant use of immunomodulators was associated with a lower adverse drug reaction-mediated discontinuation rate [aHR = 0.46; 95% CI = 0.28-0.77], in part explained by fewer infusion reactions [aHR = 0.27; 95% CI = 0.08-0.89]. In ulcerative colitis, the probability of discontinuation because of lack/loss of response was 40% [95% CI = 33%-47%] for infliximab versus 37% [95% CI = 21%-53%] for adalimumab. Disease duration ≥10 years [aHR = 0.25; 95% CI = 0.10-0.58] and normalised CRP after three months [aHR = 0.39; 95% CI = 0.18-0.84] were associated with lower discontinuation rates. CONCLUSIONS Clinical characterisation of patients may aid decision-making on anti-TNF treatment. The consistently shorter drug survival for infliximab (vs adalimumab) in Crohn's disease, suggests a potential difference between the two drugs.
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20
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Mattoo VY, Basnayake C, Connell WR, Ding N, Kamm MA, Lust M, Niewiadomski O, Thompson A, Wright EK. Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease. Aliment Pharmacol Ther 2021; 54:249-266. [PMID: 34153124 DOI: 10.1111/apt.16479] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/12/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). AIMS To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. METHODS EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. RESULTS A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. CONCLUSIONS Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.
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Affiliation(s)
- Vandita Y Mattoo
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Chamara Basnayake
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - William R Connell
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Nik Ding
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Michael A Kamm
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Mark Lust
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Ola Niewiadomski
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Alexander Thompson
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
| | - Emily K Wright
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Vic., Australia
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Paul S, Williet N, Nancey S, Veyrard P, Boschetti G, Phelip JM, Flourie B, Roblin X. No Difference of Adalimumab Pharmacokinetics When Dosed at 40 mg Every Week or 80 mg Every Other Week in IBD Patients in Clinical Remission After Adalimumab Dose Intensification. Dig Dis Sci 2021; 66:2744-2749. [PMID: 32936345 DOI: 10.1007/s10620-020-06567-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/19/2020] [Indexed: 01/06/2023]
Abstract
INTRODUCTION The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems. AIM OF THE STUDY To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. PATIENTS AND METHODS This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. RESULTS Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. CONCLUSIONS In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient's preference for the latter regimen, a modification of injection regimen should be systematically proposed.
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Affiliation(s)
- Stephane Paul
- Faculty of Medicine of Saint-Etienne, Immunology Unit University hospital of saint Etienne, CIC INSERM 1408, Saint-Etienne, France.,Groupe Immunité des muqueuses et Agents Pathogènes (GIMAP), INSERM U1111- International center for research in infectiology (CIRI), Saint-Etienne, France
| | - Nicolas Williet
- Department of Gastroenterology, Saint-Etienne University hospital, Saint-Etienne, France
| | - Stéphane Nancey
- Department of Gastroenterology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, France.,University Claude Bernard Lyon 1, Lyon, France.,INSERM U1111- International center for research in infectiology (CIRI), Lyon, France
| | - Pauline Veyrard
- Department of Gastroenterology, Saint-Etienne University hospital, Saint-Etienne, France
| | - Gilles Boschetti
- Department of Gastroenterology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, France.,University Claude Bernard Lyon 1, Lyon, France.,INSERM U1111- International center for research in infectiology (CIRI), Lyon, France
| | - Jean-Marc Phelip
- Department of Gastroenterology, Saint-Etienne University hospital, Saint-Etienne, France
| | - Bernard Flourie
- Department of Gastroenterology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, France.,University Claude Bernard Lyon 1, Lyon, France.,INSERM U1111- International center for research in infectiology (CIRI), Lyon, France
| | - Xavier Roblin
- Groupe Immunité des muqueuses et Agents Pathogènes (GIMAP), INSERM U1111- International center for research in infectiology (CIRI), Saint-Etienne, France. .,Department of Gastroenterology, Saint-Etienne University hospital, Saint-Etienne, France. .,Department of Gastroenterology, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, France.
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Ding Z, Obando C, Muser E, Kozma C, Slaton T. Real-World Persistence, Maintenance Dosing, and Pre-Post Corticosteroid and Opioid Use Among Crohn's Disease Patients with Prescription Claims for Ustekinumab in the USA. Drugs Real World Outcomes 2021; 8:565-575. [PMID: 34136998 PMCID: PMC8605940 DOI: 10.1007/s40801-021-00264-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2021] [Indexed: 12/22/2022] Open
Abstract
Background Real-world evidence for how US Crohn’s disease (CD) patients use ustekinumab is limited. Objectives The aim of this study was to describe the persistence, maintenance dosing, and pre-post corticosteroid and opioid use for CD patients in the USA treated with ustekinumab and those treated with adalimumab as a commonly used descriptive reference product. Methods CD patients aged ≥ 18 years with ≥2 CD diagnoses between 1 October 2012 and 31 May 2018 and ≥ 1 new (i.e., no claim for at least 1 year) outpatient pharmacy claim for ustekinumab or adalimumab (first claim date = index date) on or after 26 September 2016 were selected from Symphony Health database. McNemar’s tests were used to derive the p-values for pre-post changes in corticosteroid and opioid use within each treatment cohort. Results A total of 1073 ustekinumab and 2904 adalimumab patients met analysis criteria. Using a 90-day rule for discontinuation, persistence at 1 year post-index was 69.8% for ustekinumab and 65.1% for adalimumab. The majority received doses within ±30% of the approved labeling (ustekinumab 81.1%; adalimumab 78.8%). Doses higher than US package insert (PI) recommended maintenance dose were 7.0% for ustekinumab and 13.6% for adalimumab for 30% above PI, respectively; and 4.0% versus 9.4% for 50% above PI, respectively. Rates of pre-index biologic use suggest that patients treated with ustekinumab may have greater CD severity based on a greater percentage being biologic-experienced (ustekinumab 51.5% and adalimumab 8.4%). From pre- to post-index, the relative proportion of ustekinumab patients with ≥ 1 pharmacy claim for corticosteroids decreased by 25.5% (p < 0.0001) and opioids decreased by 8.4% (p = 0.0030). Results for adalimumab (a commonly used descriptive reference product in CD) showed generally similar trends. Conclusions In this real-world study, persistence for ustekinumab remained high at 1 year. The majority of the patients in the ustekinumab cohort followed US PI recommended dosing. The percentage of patients with average dose above PI recommendations over 1 year were low for ustekinumab. Reductions in the proportion of patients with claims for corticosteroids or opioids were observed in patients using ustekinumab.
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Affiliation(s)
- Zhijie Ding
- Janssen Scientific Affairs, LLC, Horsham, PA, USA.
| | | | - Erik Muser
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Chris Kozma
- Independent Consultant, St Helena Island, SC, USA
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23
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Guberna L, Nyssen OP, Chaparro M, Gisbert JP. Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis. J Clin Med 2021; 10:2132. [PMID: 34069295 PMCID: PMC8156358 DOI: 10.3390/jcm10102132] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. SELECTION prospective and retrospective studies assessing DI in Crohn's disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. EXCLUSION CRITERIA studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn's disease or those where DI was based on therapeutic drug monitoring. DATA SYNTHESIS effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn's disease), anti-TNF drug and follow-up. RESULTS One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24-32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31-47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28-43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48-78%; I2 = 99%; 32 studies) and 48% (95% CI: 39-58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents-and, consequently, DI-occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.
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Affiliation(s)
- Laura Guberna
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (L.G.); (O.P.N.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Olga P. Nyssen
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (L.G.); (O.P.N.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (L.G.); (O.P.N.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Javier P. Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain; (L.G.); (O.P.N.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
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Yamamoto-Furusho JK, Bosques-Padilla FJ, Martínez-Vázquez MA. Second Mexican consensus on biologic therapy and small-molecule inhibitors in inflammatory bowel disease. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:70-85. [PMID: 33317930 DOI: 10.1016/j.rgmx.2020.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/30/2020] [Accepted: 10/04/2020] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic and incurable entity. Therapy with anti-TNF-α agents was the first biologic therapy approved in Mexico for IBD. New biologic agents, such as vedolizumab and ustekinumab, have recently been added, as have small-molecule inhibitors. AIM To update the biologic therapeutic approach to IBD in Mexico with new anti-TNF-α agents and novel biologics whose mechanisms of action induce and maintain remission of Crohn's disease and ulcerative colitis (UC). MATERIALS AND METHODS Mexican specialists in the areas of gastroenterology and inflammatory bowel disease were summoned to participate. The consensus was divided into 3 modules, with 49 statements. The Delphi method was applied, sending the statements to all participants to be analyzed and edited, before the face-to-face meeting. During said meeting, the clinical studies were shown, emphasizing the level of clinical evidence, and the final discussion and voting round on the level of agreement of all the statements was conducted. RESULTS In this second Mexican consensus, recommendations are made for new anti-TNF-α agents, such as golimumab, new biologics with other mechanisms of action, such as vedolizumab and ustekinumab, as well as for the small-molecule inhibitor, tofacitinib. CONCLUSIONS The updated recommendations focus on patient-reported outcomes, biologic therapy, small-molecule inhibitors, and the safety aspects of each of the drugs.
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Affiliation(s)
- J K Yamamoto-Furusho
- Clínica de Enfermedad Inflamatoria Intestinal, Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.
| | - F J Bosques-Padilla
- Departamento de Gastroenterología, Hospital Universitario de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México
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Second Mexican consensus on biologic therapy and small-molecule inhibitors in inflammatory bowel disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2021. [DOI: 10.1016/j.rgmxen.2020.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Little DHW, Tabatabavakili S, Shaffer SR, Nguyen GC, Weizman AV, Targownik LE. Effectiveness of Dose De-escalation of Biologic Therapy in Inflammatory Bowel Disease: A Systematic Review. Am J Gastroenterol 2020; 115:1768-1774. [PMID: 33156094 DOI: 10.14309/ajg.0000000000000783] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION De-escalation of biologic therapy is a commonly encountered clinical scenario. Although biologic discontinuation has been associated with high rates of relapse, the effectiveness of dose de-escalation is unclear. This review was performed to determine the effectiveness of dose de-escalation of biologic therapy in inflammatory bowel disease. METHODS We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception to October 2019. Randomized controlled trials and observational studies involving dose de-escalation of biologic therapy in adults with inflammatory bowel disease in remission were included. Studies involving biologic discontinuation only and those lacking outcomes after dose de-escalation were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS We identified 1,537 unique citations with 20 eligible studies after full-text review. A total of 995 patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial. Seven studies included patients with Crohn's disease, 1 included patients with ulcerative colitis, and 12 included both. Overall, clinical relapse occurred in 0%-54% of patients who dose de-escalated biologic therapy (17 studies). The 1-year rate of clinical relapse ranged from 7% to 50% (6 studies). Eighteen studies were considered at high risk of bias, mostly because of the lack of a control group. DISCUSSION Dose de-escalation seems to be associated with high rates of clinical relapse; however, the quality of the evidence was very low. Additional controlled prospective studies are needed to clarify the effectiveness of biologic de-escalation and identify predictors of success.
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Affiliation(s)
- Derek H W Little
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | - Seth R Shaffer
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Geoffrey C Nguyen
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
| | - Adam V Weizman
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
| | - Laura E Targownik
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
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Olivares D, Alba C, Pérez I, Roales V, Rey E, Taxonera C. Differences in the need for adalimumab dose optimization between Crohn's disease and ulcerative colitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:846-851. [PMID: 31566410 DOI: 10.17235/reed.2019.6148/2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM to compare the need for and time to adalimumab dose escalation and de-escalation between patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS this observational cohort study included patients with luminal CD or patients with UC treated with adalimumab. Adalimumab dose optimization was decided based on the Harvey-Bradshaw index (CD) or the partial Mayo score (UC). The co-primary endpoints were the differences in the rate of dose escalation and the cumulative probability of escalation-free survival between cohorts. We also evaluated the rates of de-escalation and predictors of adalimumab dose escalation and de-escalation. RESULTS twenty-four of 43 CD patients (56%) and 28 of 43 UC patients (65%) required adalimumab dose escalation. UC patients had a higher adjusted rate of dose escalation (hazard ratio [HR] 2.33, 95% confidence interval [CI] 1.19-4.56; p = 0.013) than CD patients. The median time to dose escalation was significantly shorter for UC than CD patients (3.2 months, interquartile range [IQR]: 2.0-10.3 vs 12.2 months, IQR: 6.1-35.7; p = 0.001). Survival curves showed that UC patients had an increased probability of dose escalation (p < 0.001). Prior anti-TNF therapy was associated with dose escalation (HR 2.13, 95% CI 1.05-4.34; p = 0.037). Adalimumab dose de-escalation was attempted in 32% of UC patients and 50% of CD patients. Survival curves showed that CD patients had an increased probability of dose de-escalation (p = 0.030). CONCLUSION UC patients more frequently required adalimumab dose escalation than CD patients. UC patients required optimization earlier than CD patients. More CD patients than UC patients can be dose de-escalated later on during treatment.
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Affiliation(s)
- David Olivares
- Aparato Digestivo , Hospital Clínico San Carlos , España
| | - Cristina Alba
- Aparato Digestivo , Hospital Clínico San Carlos , España
| | - Irene Pérez
- Aparato Digestivo , Hospital Universitario La Paz, España
| | | | - Enrique Rey
- Aparato Digestivo, Hospital Clínico San Carlos, España
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Ehrenberg R, Griffith J, Theigs C, McDonald B. Dose Escalation Assessment Among Targeted Immunomodulators in the Management of Inflammatory Bowel Disease. J Manag Care Spec Pharm 2020; 26:758-765. [PMID: 32191593 PMCID: PMC10391226 DOI: 10.18553/jmcp.2020.19388] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND The need for individualized treatment regimens is becoming more important in the management of patients with inflammatory bowel disease (IBD). Gastroenterologists may dose adjust either by increasing the dose or shortening the dosing interval from the initial recommended maintenance dose to achieve an appropriate clinical response. Understanding the role of dose escalation in the treatment of IBD in clinical practice provides payers in the United States insight into the real-world cost-effectiveness of targeted immunomodulators (TIMs) in the management of IBD. OBJECTIVE To assess the prevalence and magnitude of dose escalation for approved IBD therapies. METHODS Using the Source Healthcare Analytics database, patients with IBD who initiated treatment with a drug of interest from July 2015 to June 2017 were identified. Patient utilization of the TIMs was tracked for 12 months following initiation. All included patients had at least 2 diagnoses for ulcerative colitis or Crohn disease before TIM initiation and at least 5 claims for a drug of interest within the 12 months following initiation. Dose escalation was defined as an increase of at least 30% in the average daily dose (ADD) relative to the patient's expected maintenance dose on 2 consecutive prescriptions. The proportion of patients with dose escalation in the first 12 months after treatment initiation was determined. The magnitude of dose escalation was determined by calculating the patient's ADD across all noninduction dose claims and comparing it with the expected daily dose. Dose escalation prevalence and magnitude were used to quantify the equivalent patient treatment rate representing the number of patients per 100 that could have been treated with standard dosing, given the prevalence of dose escalation in the treated population. RESULTS 7,028 patients (2,406 infliximab, 1,966 adalimumab, 1,745 vedolizumab, 472 ustekinumab, 285 certolizumab pegol, and 154 golimumab) met eligibility criteria and were included in the study. Among IBD therapies, dose escalation occurred most frequently with infliximab (39%), followed by adalimumab (28%), vedolizumab (23%), ustekinumab (22%), certolizumab pegol (20%), and golimumab (14%). The magnitude of dose escalation was greatest for ustekinumab (131%), followed by infliximab (70%), vedolizumab (62%), adalimumab (59%), certolizumab pegol (50%), and golimumab (45%). The calculated patient equivalence was highest for infliximab (128) and ustekinumab (128) compared with adalimumab (116), vedolizumab (114), certolizumab pegol (110), and golimumab (106). CONCLUSIONS Among patients with IBD, dose escalation occurred with all TIMs examined with varying degrees of prevalence and magnitude. Real-world utilization patterns of TIMs indicate that dose escalation is an important part of the clinical management of IBD and needs to be considered when evaluating the cost-effectiveness of IBD treatments. DISCLOSURES Financial support for this study was provided by AbbVie, which participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Ehrenberg and McDonald are employees of IQVIA, which received funding from AbbVie to participate in this research. Griffith and Theigs are employed by AbbVie and may own stock or stock options in AbbVie.
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Chapman TP, Gomes CF, Louis E, Colombel JF, Satsangi J. De-escalation of immunomodulator and biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2020; 5:63-79. [DOI: 10.1016/s2468-1253(19)30186-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
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Mastronardi M, Curlo M, Cavalcanti E, Burattini O, Cuppone R, Tauro R, De Santis S, Serino G, Pesole PL, Stasi E, Caruso ML, Donghia R, Guerra V, Giorgio P, Chieppa M. Administration Timing Is the Best Clinical Outcome Predictor for Adalimumab Administration in Crohn's Disease. Front Med (Lausanne) 2019; 6:234. [PMID: 31737635 PMCID: PMC6838026 DOI: 10.3389/fmed.2019.00234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/03/2019] [Indexed: 01/01/2023] Open
Abstract
Biological intervention for Crohn's Disease (CDs) patients, mainly using anti-TNF antibodies, is often an efficient therapeutic solution. Nonetheless, data defining the administration timing to maximize the chances of clinical remission are lacking. The objective of this “real-life” retrospective study was to evaluate if early Adalimumab (ADA) administration (<12 months) was an efficient strategy to improve patients' clinical outcome. This single center study included 157 CD patients, of which 80 received the first ADA administration within the first 12 months from the diagnosis. After 1 year of therapy, clinical remission was observed in 50.32% of patients, mucosal healing in 37.58%. Clinical remission was observed in 66.25% of the early ADA administration patients vs. 33.77% of the late (>12 months) (p < 0.001); mucosal healing was observed in 53.75% of the early vs. 20.78% of the late (p < 0.001). Dose escalation was required for 30.00% of the early vs. 66.23% of the late (<0.01). In the early ADA administration group, 7.50% patients were considered non-responders at the end of the follow-up vs. 22.08% patients in the late administration group. These findings highlighted that early ADA administration (within 1 year of diagnosis) improves the clinical response and mucosal healing, and reduces the loss of response rate and need for dose escalation.
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Affiliation(s)
- Mauro Mastronardi
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Margherita Curlo
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Elisabetta Cavalcanti
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Osvaldo Burattini
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Renato Cuppone
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Romina Tauro
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Stefania De Santis
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy.,Department of Pharmacy, Faculty of Pharmacy and Medicine, University of Salerno, Fisciano, Italy
| | - Grazia Serino
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Pasqua Letizia Pesole
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Elisa Stasi
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Maria Lucia Caruso
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Rossella Donghia
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Vito Guerra
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Pietro Giorgio
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
| | - Marcello Chieppa
- Department of Research, National Institute of Gastroenterology "S. de Bellis", Bari, Italy
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31
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Bolin K, Hertervig E, Louis E. The Cost-effectiveness of Biological Therapy Cycles in the Management of Crohn's Disease. J Crohns Colitis 2019; 13:1323-1333. [PMID: 30893421 DOI: 10.1093/ecco-jcc/jjz063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn's disease in clinical remission, with a combination of anti-tumour necrosis factor alpha [anti-TNFα] [infliximab] and immunomodulator therapy compared with two different withdrawal strategies: [1] withdrawal of the anti-TNFα therapy; and [2] withdrawal of the immunomodulator therapy, respectively. METHODS A decision-tree model was constructed mimicking three treatment arms: [1] continued combination therapy with infliximab and immunomodulator; [2] withdrawal of infliximab; or [3] withdrawal of the immunomodulator. Relapses in each arm are managed with treatment intensification and re-institution of the de-escalated drug according to a prespecified algorithm. State-dependent relapse risks, remission probabilities, and quality of life weights were collected from previous published studies. RESULTS Combination therapy was less costly and more efficient than the withdrawal of the immunomodulator, and more costly and more efficient than withdrawal of infliximab. Whether or not combination therapy is cost-effective, compared with the alternatives, depends primarily on current pharmaceutical prices and the willingness-to-pay per additional quality-adjusted life-year [QALY]. CONCLUSIONS Combination therapy using a combination of anti-TNFα [infliximab] and an immunomodulator is cost-effective in the treatment of Crohn's disease compared with treatment cycles in which the immunomodulator is withdrawn. Combination treatment is cost-effective compared with treatment cycles in which infliximab is withdrawn, at prices of infliximab below€192/100 mg, given a willingness-to-pay threshold at€49 020 [Sweden] per additional QALY.
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Affiliation(s)
- Kristian Bolin
- Department of Economics and Centre for Health Economics, Gothenburg University, Gothenburg, Sweden
| | - Erik Hertervig
- Department of Gastroenterology, Skane University Hospital, Lund, Sweden
| | - Edouard Louis
- Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium
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Swann R, Boal A, Squires SI, Lamb C, Clark LL, Lamont S, Naismith G. Optimising IBD patient selection for de-escalation of anti-TNF therapy to immunomodulator maintenance. Frontline Gastroenterol 2019; 11:16-21. [PMID: 31885835 PMCID: PMC6914296 DOI: 10.1136/flgastro-2018-101135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 04/08/2019] [Accepted: 04/08/2019] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE Inflammatory bowel disease (IBD) is increasingly managed with the use of biologic therapies. National guidelines (National Institute for Health and Care Excellence (NICE)) suggest considering cessation after 1 year of therapy but lack detailed criteria for this. We aimed to describe clinical outcomes from the introduction of a biologic review panel (BRP) to implement modified criteria for cessation of antitumour necrosis factor (anti-TNF) therapy and step down to single-agent immunomodulator. DESIGN Retrospective review of patient outcomes following BRP implementation. PATIENTS All patients on biologic therapy discussed in the BRP within a 5-year period. SETTING Single IBD network covering three hospital sites. INTERVENTIONS Modified criteria for biologic cessation were based on published evidence; they excluded individuals with no suitable maintenance immunomodulator, previous surgery or evidence of active disease, additional indications for anti-TNF therapy and previous relapse on biologic cessation. All patients with IBD on a biologic were discussed at the BRP. MAIN OUTCOME MEASURES Relapse following IBD cessation and relative cost of BRP. RESULTS 136 patients with IBD were reviewed, with 45 patients meeting the NICE guideline criteria for cessation. The BRP and modified criteria affected decision to withdraw therapy in 38% of these. Therapy was withdrawn in 27 patients, with a 20% 24-month relapse rate. Younger age at cessation was significantly associated with relapse (p=0.01). CONCLUSION The BRP approach has proved a safe and effective means of decision making in stopping biologic therapy. Future work to inform exclusion criteria is required.
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Affiliation(s)
- Rachael Swann
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Alan Boal
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Seth Ian Squires
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Carly Lamb
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Laura Louise Clark
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Selina Lamont
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
| | - Graham Naismith
- Department of Gastroenterology, Royal Alexandra Hospital, NHS Greater Glasgow and Clyde Division, Glasgow, UK
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33
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Sartini A, Scaioli E, Liverani E, Bellanova M, Ricciardiello L, Bazzoli F, Belluzzi A. Retention Rate, Persistence and Safety of Adalimumab in Inflammatory Bowel Disease: A Real-Life, 9-Year, Single-Center Experience in Italy. Dig Dis Sci 2019; 64:863-874. [PMID: 30334112 DOI: 10.1007/s10620-018-5329-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND "Real-life" data of retention rate and persistence of adalimumab in inflammatory bowel disease are still limited. AIMS To analyze retention rate, persistence, and safety of adalimumab in a 9-year real-life cohort of inflammatory bowel disease patients. METHODS In this observational, retrospective single-center study, all adult patients treated with adalimumab as the first- and second-line biological treatment for steroid-dependent or refractory inflammatory bowel disease between March 2008 and March 2017 were included. Primary outcomes were persistence, retention rate, and adverse events; the secondary outcome was the identification of predictors of withdrawal. RESULTS Ninety-six out of 181 patients (53%) withdrew their first course of adalimumab. The retention rate was 47% and 46.9% in Crohn's disease and ulcerative colitis patients, respectively; median persistence was 26 and 24 months in CD and UC patients, respectively. The cumulative probability of treatment persistence was 80.2%, 54.5%, and 29.6% and 69.6%, 40.4%, and 21.5% in CD and UC patients, respectively. The incidence rate of any adverse event was 12.5/100 patients-year; severe adverse events were 1.7/100 patients-year. The Cox regression revealed that CD patients with baseline disease duration > 72 months have a higher likelihood for withdrawal due to failure and/or adverse events (HR 1.62, 95% CI 1-2.62, p = 0.04); no predictors of discontinuation were found in UC. CONCLUSIONS Adalimumab showed a great persistence in the first 12 months of therapy and excellent safety profile. Early treatment of CD patients could increase efficacy and reduce the adverse event rate.
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Affiliation(s)
- Alessandro Sartini
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Eleonora Scaioli
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Elisa Liverani
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Matteo Bellanova
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Franco Bazzoli
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Andrea Belluzzi
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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34
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Pouillon L, Lamoureux A, Pineton de Chambrun G, Vuitton L, Pariente B, Zallot C, Dufour G, Fumery M, Baumann C, Amiot A, Nancey S, Rousseau H, Peyrin-Biroulet L. Dose de-escalation to adalimumab 40 mg every three weeks in patients with inflammatory bowel disease-A multicenter, retrospective, observational study. Dig Liver Dis 2019; 51:236-241. [PMID: 30502230 DOI: 10.1016/j.dld.2018.10.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 10/20/2018] [Accepted: 10/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data about the outcomes after adalimumab dose de-escalation in inflammatory bowel disease (IBD) are scarce. OBJECTIVES To assess the outcomes after adalimumab dose de-escalation, and to identify potential factors associated with failure. METHODS Retrospective, observational study including all IBD patients who had undergone adalimumab dose de-escalation to 40 mg every three weeks across seven GETAID centers, between June 2011 and September 2017. Failure of adalimumab dose de-escalation was defined as the need for treatment re-escalation, discontinuation of adalimumab, or clinical, biochemical and/or morphologic disease relapse. RESULTS Fifty-six patients were identified (n = 46 Crohn's disease, n = 10 ulcerative colitis). Median (IQR) duration of follow-up after adalimumab dose de-escalation was 15.9 (7.9-30.6) months. Adalimumab dose de-escalation was a failure in 21/56 (37.5%) patients and successful in 35/56 (62.5%) patients. Median (IQR) time until failure was 8.9 (4.6-15.6) months. At multivariate analysis, inactive disease at magnetic resonance imaging and/or endoscopy in the year before adalimumab dose de-escalation decreased the risk of failure with a factor five (P = 0.02). CONCLUSIONS Adalimumab dose de-escalation to 40 mg every three weeks is possible in almost two thirds of IBD patients. Objective morphologic signs of active disease should be ruled out before considering a de-escalation strategy with adalimumab.
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Affiliation(s)
- Lieven Pouillon
- INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France; Imelda GI Clinical Research Center, Imeldaziekenhuis Bonheiden, Bonheiden, Belgium
| | - Anne Lamoureux
- INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | | | - Lucine Vuitton
- Department of Gastroenterology, University Hospital of Besançon, Besançon, France
| | - Benjamin Pariente
- Department of Hepato-Gastroenterology, Claude Huriez Hospital, University of Lille-II, Lille, France
| | - Camille Zallot
- INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Gaspard Dufour
- Department of Gastroenterology and Hepatology, Saint-Eloi Hospital, Montpellier University, Montpellier, France
| | - Mathurin Fumery
- Department of Gastroenterology, Amiens University and Hospital, Université de Picardie Jules Verne, Amiens, France
| | - Cédric Baumann
- Clinical Research Support Facility PARC, UMDS, Nancy University Hospital, Vandoeuvre-lès-Nancy, France
| | - Aurélien Amiot
- Department of Gastroenterology, Henri Mondor Hospital, Paris-Est Cretain Val-de-Marne University (UPEC), Créteil, France
| | - Stéphane Nancey
- Department of Gastroenterology, Lyon-Sud Hospital, Hospices Civils of Lyon, Pierre Bénite, France; INSERM U1111 and International Center for Research in Infectiology, Lyon, France
| | - Hélène Rousseau
- Clinical Research Support Facility PARC, UMDS, Nancy University Hospital, Vandoeuvre-lès-Nancy, France
| | - Laurent Peyrin-Biroulet
- INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France.
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Vázquez Morón JM, Rodríguez Moncada R, Pallarés Manrique H. Intravenous ustekinumab reinduction as a Crohn�s disease rescue strategy following a secondary non-response. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2019; 111:721. [DOI: 10.17235/reed.2019.5802/2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Attar A, Duru G, Roblin X, Savarieau B, Brunel P, Lamure M, Peyrin-Biroulet L. Cost savings using a test-based de-escalation strategy for patients with Crohn's disease in remission on optimized infliximab: A discrete event model study. Dig Liver Dis 2019; 51:112-119. [PMID: 30268737 DOI: 10.1016/j.dld.2018.08.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/24/2018] [Accepted: 08/27/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Drug de-escalation is considered in Crohn's disease patients in sustained remission on optimized infliximab treatment. AIM We built a model to evaluate the magnitude of cost savings in patients' disease course with or without drug de-escalation guided by infliximab trough levels. METHODS We designed 4 virtual cohorts (P1-P4) of 10,000 patients in clinical remission on optimized infliximab treatment followed for 2 years. P1: no drug de-escalation - 10 mg/kg/8 weeks; P2: drug de-escalation from 10 mg/kg/8 weeks to 5 mg/kg/8 weeks according to trough levels; P3: no drug de-escalation - 10 mg/kg/6 weeks; and P4: drug de-escalation from 10 mg/kg/6 weeks to 10 mg/kg/8 weeks according to trough levels. For P2 and P4 cohorts, drug de-escalation was decided if trough levels were ≥7 μg/mL and no de-escalation if trough levels were <7 μg/mL. Only costs related to drug administration were considered. RESULTS The cost differences when comparing P1 versus P2 and P3 versus P4 were 7.6% and 4.6%, respectively, corresponding to costs savings of €30.5 millions and €20.3 million for 10,000 patients. CONCLUSION Over a 2-year period, infliximab de-escalation according to trough levels led to cost saving of about 6%, corresponding to around €25.4 million.
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Affiliation(s)
- Alain Attar
- Department of Gastroenterology - IBD - Nutritional Support, Beaujon Hospital, Clichy, France.
| | - Gérard Duru
- University Lyon 1, University of Lyon, France
| | - Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint-Etienne, France
| | | | - Pierre Brunel
- Department of Pharmacy, University Hospital of Saint Etienne, France
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Tanaka H, Kamata N, Yamada A, Endo K, Fujii T, Yoshino T, Sugaya T, Yokoyama Y, Bamba S, Umeno J, Yanai Y, Ishii M, Kawaguchi T, Shinzaki S, Toya Y, Kobayashi T, Nojima M, Hibi T. Long-term retention of adalimumab treatment and associated prognostic factors for 1189 patients with Crohn's disease. J Gastroenterol Hepatol 2018; 33:1031-1038. [PMID: 29087616 DOI: 10.1111/jgh.14034] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 10/01/2017] [Accepted: 10/23/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM There are few studies on the long-term efficacy of adalimumab treatment for patients with Crohn's disease. We have conducted a large, multicenter, retrospective cohort study to evaluate the long-term retention rate and prognostic factors associated with the discontinuation of adalimumab treatment in patients with Crohn's disease. METHODS Data were collected from all patients with Crohn's disease who had received at least one induction dose of 160 mg of adalimumab between October 2010 and December 2013 at 41 institutions. The cumulative retention rates of adalimumab treatment following the first administration were estimated using the Kaplan-Meier method. Prognostic factors related to the cumulative retention rates were evaluated by log-rank tests and multivariate Cox regression analysis. RESULTS A total of 1189 patients were included in the study. The 1-, 2-, 3-, and 4-year cumulative retention rates of adalimumab were 81%, 72%, 65%, and 62%, respectively. The multivariate Cox regression analysis confirmed female sex, previous infliximab use, perianal disease, concomitant treatment with prednisolone at baseline, higher C-reactive protein levels, and lower albumin levels as significant independent predictors of poor retention rate of adalimumab treatment. Significantly, more female patients than male patients discontinued adalimumab because of adverse events, especially skin reactions, infections, and arthralgia. CONCLUSIONS Our data demonstrated a good retention rate of adalimumab in patients with Crohn's disease over a 4-year period. Female sex, perianal disease, concomitant treatment with prednisolone at baseline, previous infliximab use, higher C-reactive protein levels, and lower albumin levels were associated with poor retention of adalimumab treatment.
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Affiliation(s)
- Hiroki Tanaka
- IBD Center, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Yamada
- Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan
| | - Katsuya Endo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takuya Yoshino
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,IBD Center, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Takeshi Sugaya
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Japan
| | - Yoko Yokoyama
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shigeki Bamba
- Division of Gastroenterology, Shiga University of Medical Science, Shiga, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuka Yanai
- Department of Gastroenterology, Oita Red Cross Hospital, Oita, Japan
| | - Manabu Ishii
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, Kurashiki, Japan
| | - Takaaki Kawaguchi
- Department of Internal Medicine, Division of IBD, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yosuke Toya
- Division of Gastroenterology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Van de Vondel S, Baert F, Reenaers C, Vanden Branden S, Amininejad L, Dewint P, Van Moerkercke W, Rahier JF, Hindryckx P, Bossuyt P, Ferrante M. Incidence and Predictors of Success of Adalimumab Dose Escalation and De-escalation in Ulcerative Colitis: a Real-World Belgian Cohort Study. Inflamm Bowel Dis 2018; 24:1099-1105. [PMID: 29668947 DOI: 10.1093/ibd/izx103] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. METHODS We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up ≥1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success of dose escalation, and dose de-escalation. Backward Cox regression and Wald Logistic regression were used to identify predictive variables. RESULTS Short-term clinical benefit was achieved in 101 patients (44%) and was less frequent in infliximab failures [37% vs 50%, Odds ratio 0.57 (95% CI 0.34-0.97), P = 0.038]. After a median of 2.8 (1.7-5.1) months, 164 patients (71%) needed ADM discontinuation (n = 35, 15%) or dose escalation (n = 129, 56%). Dose escalation was successful in 77/129 (60%). Dose de-escalation was attempted in 71% (55/77) after a median of 4.3 (2.9-7.2) months and was successful in 80% (43/54). CONCLUSIONS In this cohort, 56% of patients with UC required ADM dose escalation with a 60% success rate. Of note, most patients could be successfully de-escalated later on.
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Affiliation(s)
- Saartje Van de Vondel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Filip Baert
- Department of Gastroenterology, AZ Delta, Roeselare, Belgium
| | - Christine Reenaers
- Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium
| | | | - Leila Amininejad
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Pieter Dewint
- Department of Gastroenterology, AZ Maria Middelares, Ghent, Belgium
| | | | | | - Pieter Hindryckx
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Peter Bossuyt
- Department of Gastroenterology, Imelda Hospital, Bonheiden, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, Mao R, Berset IP, Gisbert JP, Sebastian S, Kierkus J, Lopetuso L, Szymanska E, Louis E. European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease. J Crohns Colitis 2018; 12:17-31. [PMID: 28981623 DOI: 10.1093/ecco-jcc/jjx101] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/31/2017] [Indexed: 12/12/2022]
Abstract
Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications [5-aminosalicyclates, immunomodulators, and biologic agents], used alone or in combination, there is a risk of relapse following reduction or cessation of treatment. A consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the published literature and agreed a series of consensus practice points. The objective of the expert consensus is to provide evidence-based guidance for clinical practice so that physicians can make informed decisions in partnership with their patients. The likelihood of relapse with stopping each class of IBD medication is reviewed. Factors associated with an altered risk of relapse with withdrawal are evaluated, and strategies to monitor and allow early identification of relapse are considered. In general, patients in clinical, biochemical, and endoscopic remission are more likely to remain well when treatments are stopped. Reintroduction of the same treatment is usually, but not always, successful. The decision to stop a treatment needs to be individualized, and shared decision making with the patient should take place.
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Affiliation(s)
- Glen Doherty
- Centre for Colorectal Disease, St Vincent's University Hospital & University College Dublin, Dublin, Ireland
| | - Konstantinos H Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Johan Burisch
- Department of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark
| | - Matthieu Allez
- Department of Gastroenterology and Hepatology, Hôpital Saint-Louis, APHP, INSERM UMRS 1160, Université Denis Diderot, Paris, France
| | | | - Andreas Stallmach
- Department of Internal Medicine IV [Gastroenterology, Hepatology and Infectious Disease], University Hospital Jena, Jena, Germany
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ingrid Prytz Berset
- Gastroenterology Department, Alesund Hospital, Helse More Romsdal Hospital Trust, Alesund, Norway
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de la Princesa, Instituto de Investigaciun Sanitaria Princesa (IIS-IP) and Centro de Investigaciun Biomédica en Red de Enfermedades Heprticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Shaji Sebastian
- IBD Unit, Department of Gastroenterology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Loris Lopetuso
- Department of Gastroenterology and Internal Medicine, Catholic University of Rome-A. Gemelli Hospital, Rome, Italy
| | - Edyta Szymanska
- Department of Pediatrics, Nutrition, and Metabolic Disorders, Children's Memorial Health Institute, Warsaw, Poland
| | - Edouard Louis
- Department of Gastroenterology, CHU Liège, Sart Tilman, Liège, Belgium
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40
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Rentsch C, Headon B, Ward MG, Gibson PR. Inadequate storage of subcutaneous biological agents by patients with inflammatory bowel disease: Another factor driving loss of response? J Gastroenterol Hepatol 2018; 33:10-11. [PMID: 29284080 DOI: 10.1111/jgh.14001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 09/14/2017] [Indexed: 12/09/2022]
Affiliation(s)
- C Rentsch
- Departments of Pharmacy, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - B Headon
- Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - M G Ward
- Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - P R Gibson
- Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
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41
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Seo H, Ye BD, Song EM, Lee SH, Chang K, Lee HS, Hwang SW, Park SH, Yang DH, Kim KJ, Byeon JS, Myung SJ, Yang SK. Long-Term Outcomes of Adalimumab Treatment in 254 Patients with Crohn's Disease: A Hospital-Based Cohort Study from Korea. Dig Dis Sci 2017; 62:2882-2893. [PMID: 28822006 DOI: 10.1007/s10620-017-4715-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Large-scale studies regarding the long-term outcomes of adalimumab (ADA) treatment in Asian patients with Crohn's disease (CD) are still scarce. METHODS We retrospectively analyzed the long-term outcomes of ADA treatment in Korean CD patients who commenced on scheduled ADA treatment at Asan Medical Center between November 2008 and July 2016. Clinical response was defined as maintaining ADA treatment without dose intensification (DI) and/or major abdominal surgery (MAS). RESULTS Of the 254 patients who received at least two doses of ADA at 2-week intervals as induction therapy, 250 patients (98.4%) showed an initial favorable response by week 4. Among responders, 243 patients were followed up for longer than 4 weeks and were included for further analysis. The median duration of ADA maintenance therapy was 19.4 months. At the last follow-up, 45 patients (18.5%) required DI after a median of 16.8 months and 31 (12.8%) required MAS after a median of 8.9 months. Finally, 161 patients (66.3%) were still receiving ADA without DI and/or MAS. The cumulative probability of maintaining ADA without DI and/or MAS was 81.1% at 1 year, and 36.5% at 5 years. Secondary loss of response to previous infliximab (P = 0.001) and elevated baseline C-reactive protein at starting ADA treatment (P = 0.008) were identified as independent predictors of a poor response to ADA treatment using multivariate regression analysis. CONCLUSIONS The long-term outcome of ADA treatment in a real-life cohort of Korean patients with CD appears to be comparable to that reported in previously published Western studies.
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Affiliation(s)
- Hyungil Seo
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. .,Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
| | - Eun Mi Song
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Sun-Ho Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Kiju Chang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Ho-Su Lee
- Health Screening and Promotion Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.,Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.,Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.,Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.,Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Lopetuso LR, Gerardi V, Papa V, Scaldaferri F, Rapaccini GL, Gasbarrini A, Papa A. Can We Predict the Efficacy of Anti-TNF-α Agents? Int J Mol Sci 2017; 18:ijms18091973. [PMID: 28906475 PMCID: PMC5618622 DOI: 10.3390/ijms18091973] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/05/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022] Open
Abstract
The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side-effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost-effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-α therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Viviana Gerardi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Valerio Papa
- Digestive Surgery Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy;
| | - Franco Scaldaferri
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
- Correspondence: ; Tel.: +39-06-3503310
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Kariyawasam VC, Ward MG, Blaker PA, Patel KV, Goel R, Sanderson JD, Irving PM. Thiopurines Dosed to a Therapeutic 6-Thioguanine Level in Combination with Adalimumab Are More Effective Than Subtherapeutic Thiopurine-based Combination Therapy or Adalimumab Monotherapy During Induction and Maintenance in Patients with Long-standing Crohn's Disease. Inflamm Bowel Dis 2017; 23:1555-1565. [PMID: 28786865 DOI: 10.1097/mib.0000000000001183] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohn's disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs). METHODS Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 10 red blood cell therapeutic). RESULTS At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41-13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01-1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87-7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08-0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure. CONCLUSIONS Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.
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Affiliation(s)
- Viraj C Kariyawasam
- *Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom; and †Western Sydney University, Blacktown Clinical School, Blacktown, Australia
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Einarson TR, Bereza BG, Ying Lee X, Lelli F. Dose escalation of biologics in Crohn's disease: critical review of observational studies. Curr Med Res Opin 2017; 33:1433-1449. [PMID: 28537467 DOI: 10.1080/03007995.2017.1335001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Biologics used to treat Crohn's disease (CD) may lose their effect over time, requiring dose escalation. Little information is available on this topic. AIM To summarize rates of dose escalation, duration, de-escalation in observational studies of CD in adults treated with adalimumab, infliximab, and vedolizumab in Europe. METHODS Two independent investigators searched Medline and Embase for observational studies published in 1998-2015 and proceedings from four major scientific meetings. Rates were summarized descriptively. RESULTS In total, 58 articles from 12 European countries were analyzed (49 full articles, nine abstracts), providing 65 reports with 7,850 patients; 35 reported on 3,830 patients with adalimumab (ADA), and 30 on 4,020 patients with infliximab (IFX). Overall, 29.9% ± 3.5% of patients required dose escalation; 32.8% ± 6.2% with ADA and 25.2% ± 2.4% with IFX (p = .35 between drugs). Rates increased according to line of treatment: 19% for first line, 37% second, and 41% third. The median time to loss of response was 12 months, and the weighted average was 15.1 ± 5.9 months. Median time to escalation was 6.7 months; 6.7 months for ADA and 7.5 for IFX (p = .86). Short-term response rates to escalation were 63% for ADA and 45% for IFX (p = .08). There were no papers available for vedolizumab. CONCLUSIONS A substantial proportion of patients receiving ADA or IFX for Crohn's disease require dose escalation after a short period of time.
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Affiliation(s)
- Thomas R Einarson
- a Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada
| | - Basil G Bereza
- a Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada
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45
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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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46
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Qiu Y, Chen BL, Mao R, Zhang SH, He Y, Zeng ZR, Ben-Horin S, Chen MH. Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn's disease. J Gastroenterol 2017; 52:535-554. [PMID: 28275925 DOI: 10.1007/s00535-017-1324-3] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/21/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND To review the frequency with which anti-TNF-α loses its effect and dose "intensification" is required for Crohn's disease (CD) treatment. METHODS Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS Eighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29-38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22-39) for adalimumab, and 41% (95% CI 30-53) for certolizumabpegol. Overall, the mean percentage of patients' LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28-41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28-50), 36% (95% CI 30-43) for adalimumab, and 2% (95% CI 2-3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001). CONCLUSIONS Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.
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Affiliation(s)
- Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Bai-Li Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Sheng-Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Yao He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Zhi-Rong Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Shomron Ben-Horin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.,IBD Service, Department of Gastroenterology, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, 52621, Tel Hashomer, Israel
| | - Min-Hu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
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Van Steenbergen S, Bian S, Vermeire S, Van Assche G, Gils A, Ferrante M. Dose de-escalation to adalimumab 40 mg every 3 weeks in patients with Crohn's disease - a nested case-control study. Aliment Pharmacol Ther 2017; 45:923-932. [PMID: 28164321 DOI: 10.1111/apt.13964] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 01/06/2017] [Accepted: 01/11/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data on dose de-escalation in patients with Crohn's disease (CD) are limited. AIM To evaluate outcomes of dose de-escalation from adalimumab (ADM) every other week (EOW) to every three weeks (ETW). METHODS We selected patients with CD receiving maintenance therapy with ADM 40 mg ETW with serum levels (SL) available before and after dose de-escalation. Sex- and age-matched controls continuing ADM 40 mg EOW were identified. Patient reported outcome, C-reactive protein (CRP) and serum albumin were collected. RESULTS Out of 898 patients, we identified 40 (11 male, median 37 years) who de-escalated to ADM 40 mg ETW for ADM-related adverse events (AE, n = 1), ADM SL >7 μg/mL (n = 8), or both (n = 31). Compared to controls, ADM SL dropped significantly within 4 months, without associated clinical or biochemical changes. In 53% of patients, dose de-escalation was associated with disappearance of AE (8/16 skin manifestation, 3/6 arthralgia, 5/7 frequent infectious episodes). During a median follow-up of 24 months, 65% of patients maintained clinical response, but 35% needed dose escalation back to ADM 40 mg EOW because of clinical relapse (n = 8), ADM SL <4 μg/mL (n = 2), or both (n = 4). CRP <3.5 mg/L at dose de-escalation was independently associated with dose escalation-free survival [odds ratio 6.28 (95% CI 1.83-21.59), P = 0.004]. We could not define a minimal ADM SL to consider or maintain dose de-escalation. CONCLUSIONS Overall, 65% of patients who de-escalated to adalimumab 40 mg every 3 weeks remained in clinical remission for a median of 24 months. In 53% of patients, adalimumab-related adverse events disappeared after dose de-escalation. Regardless of adalimumab SL, disease remission should be assessed objectively prior to dose de-escalation.
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Affiliation(s)
- S Van Steenbergen
- Department of General Practice, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - S Bian
- Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - S Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - G Van Assche
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - A Gils
- Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - M Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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48
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Duveau N, Nachury M, Gerard R, Branche J, Maunoury V, Boualit M, Wils P, Desreumaux P, Pariente B. Adalimumab dose escalation is effective and well tolerated in Crohn's disease patients with secondary loss of response to adalimumab. Dig Liver Dis 2017; 49:163-169. [PMID: 27899263 DOI: 10.1016/j.dld.2016.11.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 10/09/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although adalimumab is effective in Crohn's disease, most patients experience a loss of response over time. The aim of the present study was to evaluate efficacy and safety of adalimumab dose escalation and identify predictors of a clinical response in Crohn's disease patients with a secondary loss of response. METHODS We performed a retrospective and observational study including all Crohn's disease patients who underwent dose escalation of adalimumab after a secondary loss of response from 2007 to 2015. RESULTS A clinical response was observed in 99/124 (79%) patients at 3 months and in 62/107 (61%) patients at 12 months. The predictive factors of response to ADA dose escalation at 12 months on multivariate analysis were: maintenance therapy of 40mg every week rather than 80mg every other week (OR 3.64, 95% CI: 1.28-10.37) and a CRP level≤5mg/L at adalimumab dose escalation (OR 6.64, 95% CI: 1.40-27.53). Adalimumab was withdrawn in 4 patients due to side effects. CONCLUSIONS Adalimumab dose escalation is an effective and well-tolerated therapeutic option in patients with secondary loss of response. A 40mg every week optimized regimen was predictive of a response to ADA dose escalation.
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Affiliation(s)
- Nicolas Duveau
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Maria Nachury
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Romain Gerard
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Julien Branche
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Vincent Maunoury
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Medina Boualit
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Pauline Wils
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Pierre Desreumaux
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France
| | - Benjamin Pariente
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France.
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49
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Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review. J Gastroenterol 2017; 52:19-25. [PMID: 27665099 DOI: 10.1007/s00535-016-1266-1] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 09/12/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) of anti-TNF is increasingly used to manage inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA). The cost-effectiveness of this strategy is debated. METHODS All studies comparing the cost-effectiveness of a TDM-based strategy and an empirical dose management of anti-TNF in IBD or RA were screened. Studies were identified through the MEDLINE electronic database (up to July 2016), and annual international meeting abstracts were also manually reviewed. RESULTS Seven studies were included: two randomized controlled trials (RCTs) enrolling 332 patients [247 Crohn's disease (CD) and 85 ulcerative colitis (UC)] and five modeling approaches. Four studies included only CD patients, one included both CD and UC patients, and two included only RA patients. Three studies compared the cost-effectiveness of the two strategies in patients with secondary infliximab (IFX) failure (dose-escalation strategy), one in patients in remission on optimized IFX (de-escalation strategy), one in patients starting adalimumab, and two in patients with clinical response to maintenance anti-TNF therapy. The two RCTs demonstrated that a TDM strategy led to major cost savings, ranging from 28 to 34 %. The three modeling approaches with regard to CD patients demonstrated cost savings ranging from $5396 over a 1-year period to €13,130 per patient at 5 years of follow-up. A TDM strategy also led to major cost savings in the two modeling approaches in RA patients. CONCLUSIONS Available evidence indicates that a TDM strategy leads to major cost savings related to anti-TNF therapy in both IBD and RA patients, with no negative impact on efficacy.
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Ungar B, Kopylov U, Engel T, Yavzori M, Fudim E, Picard O, Lang A, Williet N, Paul S, Chowers Y, Bar-Gil Shitrit A, Eliakim R, Ben-Horin S, Roblin X. Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther 2017; 45:276-282. [PMID: 27862102 DOI: 10.1111/apt.13862] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 09/15/2016] [Accepted: 10/24/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anti-adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. AIM To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. METHODS The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as 'sero-reversal', elevation of drug levels and regained clinical response were the sought outcomes. RESULTS Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. CONCLUSIONS In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies.
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Affiliation(s)
- B Ungar
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - U Kopylov
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - T Engel
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Yavzori
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - E Fudim
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - O Picard
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - A Lang
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - N Williet
- Service de Gastrologie-Entérologie-Hépatologie, CHU de Saint-Etienne, Saint-Etienne, France
| | - S Paul
- Service de Gastrologie-Entérologie-Hépatologie, CHU de Saint-Etienne, Saint-Etienne, France
| | - Y Chowers
- Rambam Health Care Campus, Bruce & Ruth Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel
| | - A Bar-Gil Shitrit
- Digestive Diseases Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - R Eliakim
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - S Ben-Horin
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - X Roblin
- Service de Gastrologie-Entérologie-Hépatologie, CHU de Saint-Etienne, Saint-Etienne, France
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