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González-Lama Y, Ricart E, Carpio D, Bastida G, Ceballos D, Ginard D, Marin-Jimenez I, Menchen L, Muñoz F. Controversies in the management of anti-TNF therapy in patients with Crohn's disease: a Delphi consensus. BMJ Open Gastroenterol 2024; 11:e001246. [PMID: 38267072 PMCID: PMC10870792 DOI: 10.1136/bmjgast-2023-001246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/24/2023] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Despite research, there are still controversial areas in the management of Crohn's disease (CD). OBJECTIVE To establish practical recommendations on using anti-tumour necrosis factor (TNF) drugs in patients with moderate-to-severe CD. METHODS Clinical controversies in the management of CD using anti-TNF therapies were identified. A comprehensive literature review was performed, and a national survey was launched to examine current clinical practices when using anti-TNF therapies. Their results were discussed by expert gastroenterologists within a nominal group meeting, and a set of statements was proposed and tested in a Delphi process. RESULTS Qualitative study. The survey and Delphi process were sent to 244 CD-treating physicians (response rate: 58%). A total of 14 statements were generated. All but two achieved agreement. These statements cover: (1) use of first-line non-anti-TNF biological therapy; (2) role of HLA-DQA1*05 in daily practice; (3) attitudes in primary non-response and loss of response to anti-TNF therapy due to immunogenicity; (4) use of ustekinumab or vedolizumab if a change in action mechanism is warranted; (5) anti-TNF drug level monitoring; (6) combined therapy with an immunomodulator. CONCLUSION This document sought to pull together the best evidence, experts' opinions, and treating physicians' attitudes when using anti-TNF therapies in patients with CD.
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Affiliation(s)
- Yago González-Lama
- Gastroenterology Department, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
| | - Elena Ricart
- Gastroenterology Department, CIBEREHD, Madrid, Spain
| | - Daniel Carpio
- Gastroenterology Department, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | | | - Daniel Ceballos
- Gastroenterology Department, Hospital Universitario Doctor Negrin, Las Palmas de Gran Canaria, Spain
| | - Daniel Ginard
- Gastroenterology Department, Hospital Universitario Son Espases, Palma, Spain
| | | | - Luis Menchen
- Gastroenterology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Fernando Muñoz
- Gastroenterology Department, Hospital Universitario de Salamanca, Salamanca, Spain
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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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Orfanoudaki E, Foteinogiannopoulou K, Theodoraki E, Koutroubakis IE. Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12072452. [PMID: 37048536 PMCID: PMC10095227 DOI: 10.3390/jcm12072452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.
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Affiliation(s)
- Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Kalliopi Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini Theodoraki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
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Singh H, Wilson L, Tencer T, Kumar J. Systematic Literature Review of Real-World Evidence on Dose Escalation and Treatment Switching in Ulcerative Colitis. CLINICOECONOMICS AND OUTCOMES RESEARCH 2023; 15:125-138. [PMID: 36855750 PMCID: PMC9968424 DOI: 10.2147/ceor.s391413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/24/2023] [Indexed: 02/24/2023] Open
Abstract
Background Currently approved biologic therapies for moderate-to-severe ulcerative colitis have well-established efficacy. However, many patients fail to respond or lose response, leading to dose escalation or treatment switching. Objective We sought to identify real-world evidence on dose escalation and treatment switching and associated clinical and economic outcomes among adults with ulcerative colitis treated with infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, or tofacitinib. Methods We conducted a systematic search of Embase, MEDLINE (up to 26 August 2020), and conference proceedings (2017-2020) for studies in adults with ulcerative colitis to assess clinical response and remission, colectomy, adverse events, and economic outcomes related to dose escalation and treatment switching. Results In 56 studies, dose escalation and treatment switching involving infliximab and/or adalimumab were most frequently investigated. Rates of clinical response after dose escalation were 20-95% (1.8-36 months), clinical remission rates were 10-94% (1.8-36 months), colectomy rates were 0-33% (12-38 months), and adverse event rates were 0-18%. Treatment switching rates in 21 studies were 4-70% over 3-62 months, with switch due to loss of response rates of 4-35% over 12-62 months (7 studies). Up to 35% of patients underwent colectomy 12-120 weeks after switching, and 13-38% experienced adverse events. Data relating to economic outcomes were limited to tumor necrosis factor inhibitors, but demonstrated increased direct costs associated with both dose escalation and treatment switching. Conclusion Dose escalation and treatment switching are common with existing therapies. However, clinical response and remission rates vary, and a proportion of patients fail to achieve optimal clinical and economic outcomes. This highlights the need for more efficacious and durable treatments for patients with moderate-to-severe ulcerative colitis.
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Affiliation(s)
- Harpreet Singh
- Health Economics & Market Access (HEMA), Amaris Consulting Ltd, Toronto, ON, Canada
| | - Liam Wilson
- Health Economics & Market Access (HEMA), Amaris Consulting Ltd, Shanghai, People’s Republic of China
| | - Tom Tencer
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Jinender Kumar
- Bristol Myers Squibb, Princeton, NJ, USA,Correspondence: Jinender Kumar, Global HEOR, Bristol Myers Squibb, 100 Nassau Park Blvd #300, Princeton, NJ, 08540, USA, Tel +1-609-302-7630, Email
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Nakase H, Esaki M, Hirai F, Kobayashi T, Matsuoka K, Matsuura M, Naganuma M, Saruta M, Tsuchiya K, Uchino M, Watanabe K, Hisamatsu T. Treatment escalation and de-escalation decisions in Crohn's disease: Delphi consensus recommendations from Japan, 2021. J Gastroenterol 2023; 58:313-345. [PMID: 36773075 PMCID: PMC10050046 DOI: 10.1007/s00535-023-01958-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/08/2023] [Indexed: 02/12/2023]
Abstract
BACKGROUND We aimed to develop criteria for treatment intensification in patients with (1) luminal Crohn's disease (CD), (2) CD with perianal disease and/or fistula, (3) CD with small bowel stenosis, (4) in the postoperative setting, and (5) for discontinuing or reducing the dose of treatment in patients with CD. METHODS PubMed and Embase were searched for studies published since 1998 which may be relevant to the five defined topics. Results were assessed for relevant studies, with preference given to data from randomized, controlled studies. For each question, a core panel of 12 gastroenterologists defined the treatment target and developed statements, based on the literature, current guidelines, and relevant additional studies. The evidence supporting each statement was graded using the Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). A modified Delphi process was used to refine statements and gain agreement from 54 Japanese specialists at in-person and online meetings conducted between October 2020 and April 2021. RESULTS Seventeen statements were developed for treatment intensification in luminal CD (targeting endoscopic remission), six statements for treatment intensification in perianal/fistulizing CD (targeting healing of perianal lesions and complete closure of the fistula), six statements for treatment intensification in CD with small bowel stenosis (targeting resolution of obstructive symptoms), seven statements for treatment intensification after surgery (targeting endoscopic remission), and five statements for discontinuing or reducing the dose of treatment in patients with CD. CONCLUSIONS These statements provide guidance on how and when to intensify or de-intensify treatment for a broad spectrum of patients with CD.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo, Hokkaido 060-8543 Japan
| | - Motohiro Esaki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611 Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Motoi Uchino
- Division of Inflammatory Bowel Disease, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Hyogo Japan
| | - Kenji Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Hyogo Japan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611 Japan
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Mahmoud R, Schultheiss JPD, Fidder HH, Oldenburg B. Reply. Clin Gastroenterol Hepatol 2023; 21:558-559. [PMID: 35483605 DOI: 10.1016/j.cgh.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Remi Mahmoud
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Johannes P D Schultheiss
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Herma H Fidder
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
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7
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Giri S, Ingawale S, Angadi S. Immunomodulator Withdrawal From Anti-TNF Therapy Needs a Careful Patient Selection. Clin Gastroenterol Hepatol 2023; 21:557-558. [PMID: 35151860 DOI: 10.1016/j.cgh.2022.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Suprabhat Giri
- Department of Gastroenterology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Sushrut Ingawale
- Department of General Medicine, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Sumaswi Angadi
- Department of Gastroenterology, Nizam's Institute of Medical Sciences, Hyderabad, India
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Mahmoud R, Schultheiss HP, Louwers J, van der Kaaij M, van Hellemondt B, Mahmmod N, van Boeckel P, Jharap B, Fidder H, Oldenburg B. Immunomodulator Withdrawal From Anti-TNF Therapy Is Not Associated With Loss of Response in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2022; 20:2577-2587.e6. [PMID: 35101632 DOI: 10.1016/j.cgh.2022.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The benefit of concomitant immunomodulators (thiopurines or methotrexate) in patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor α (anti-TNF) (infliximab or adalimumab) maintenance therapy is debated. We compared outcomes after immunomodulator withdrawal vs continuation of combination therapy. METHODS This was a retrospective cohort study in a general hospital and a tertiary referral center. We included adult IBD patients, receiving anti-TNF therapy for ≥4 months, plus an immunomodulator at baseline, between January 1, 2011, and January 1, 2019. The primary endpoints were loss of response (LOR) (ie, anti-TNF discontinuation because of disease activity) and anti-drug antibodies. Adjusted hazard ratios (aHRs) were calculated by mixed-effects Cox regression analysis. RESULTS We included 614 treatment episodes of combination therapy in 543 individuals, yielding 1664 patient-years of follow-up. The immunomodulator was withdrawn in 296 (48.2%) episodes after 0.9 (interquartile range, 0.6-2.1) years, which was not associated with a higher risk of LOR (aHR, 1.08; 95% confidence interval [CI], 0.72-1.61), although anti-drug antibodies were detected more frequently (aHR, 2.14; 95% CI, 1.17-3.94), compared with continuation. Clinical remission at the time of withdrawal reduced the risk of LOR (aHR, 0.48; 95% CI, 0.25-0.93), while longer duration of combination therapy before withdrawal decreased the risk of anti-drug antibodies (HR per year, 0.56; 95% CI, 0.32-0.91). Higher prewithdrawal infliximab trough levels reduced the subsequent risks of anti-drug antibodies and LOR. Infliximab trough levels were lower after immunomodulator withdrawal (P = .01). CONCLUSIONS Patients who withdrew the immunomodulator in this retrospective cohort were not at increased risk of LOR within the following 1-2 years, but an increase in anti-drug antibodies was observed. Our findings require prospective validation, preferably in adequately powered randomized controlled trials.
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Affiliation(s)
- Remi Mahmoud
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hans-Paul Schultheiss
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jonas Louwers
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Michiel van der Kaaij
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Boris van Hellemondt
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Nofel Mahmmod
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, the Netherlands
| | - Petra van Boeckel
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, the Netherlands
| | - Bindia Jharap
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Meander Medical Center, Amersfoort, the Netherlands
| | - Herma Fidder
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Bas Oldenburg
- Division of Internal Medicine and Dermatology, Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands.
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Cohen HP, Hachaichi S, Bodenmueller W, Kvien TK, Danese S, Blauvelt A. Switching from One Biosimilar to Another Biosimilar of the Same Reference Biologic: A Systematic Review of Studies. BioDrugs 2022; 36:625-637. [PMID: 35881304 PMCID: PMC9485085 DOI: 10.1007/s40259-022-00546-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Multiple switches (transitions) between biosimilars of the same reference biologic are now a reality, and they are expected to become more common in the future as more biosimilars enter the market. Switching between two biosimilars of the same reference biologic is generally driven by affordability, formulary requirements, or the relocation/travel of the patient. Evidence of whether switching between biosimilars of the same reference biologic provides similar safety and efficacy profiles is reviewed here. METHODS A systematic search was undertaken using electronic databases (to December 2021): Biosis, Embase, MEDLINE, and EBM Reviews/Cochrane Database of Systematic Reviews via Ovid. Publications were evaluated for effectiveness and/or safety data linked to switching from one biosimilar to another. RESULTS The systematic search yielded 982 citations. After eliminating duplicates, 626 citations remained for the initial title/abstract screening phase. Following the initial screening, 240 records were chosen; more thorough examination yielded 35 citations. After comprehensive screening and expert advice, 23 studies were selected, of which 13 were published in peer-reviewed journals; the remainder have been published as abstracts. Overall, 3657 patients were included in these studies. All studies were observational in nature; no randomized clinical trials were identified. The studies were heterogeneous in size, design, and endpoints. Across the studies, data are provided on safety, effectiveness, immunogenicity, pharmacokinetics, patient retention, patient and physician perceptions, and drug-use patterns. The majority of studies examined switches between biosimilar infliximabs, although switches between biosimilar adalimumabs, etanercepts, and rituximabs were also identified. Two use-pattern studies and one case report were also detected and are discussed. CONCLUSION Within the limitations of this systematic review, available data suggests that biosimilar-to-biosimilar switching is a safe and effective clinical practice, although it is not covered by current health authority regulations or guidance. No reduction in effectiveness or increase in adverse events was detected in biosimilar-to-biosimilar switching studies conducted to date.
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Affiliation(s)
- Hillel P Cohen
- Sandoz Inc. (A Novartis Division), 100 College Road West, Princeton, NJ, 08540, USA.
| | | | | | - Tore K Kvien
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
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10
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Jeong TJ, Kim ES, Kwon Y, Kim S, Seo SW, Choe YH, Kim MJ. Discontinuation of Azathioprine could be considered in pediatric patients with Crohn's disease who have sustained clinical and deep remission. Sci Rep 2022; 12:507. [PMID: 35017546 PMCID: PMC8752804 DOI: 10.1038/s41598-021-04304-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 12/14/2021] [Indexed: 11/09/2022] Open
Abstract
Few studies have demonstrated treatment strategies about the duration and cessation of medications in patients with Crohn's disease (CD). We investigated factors affecting clinical relapse after infliximab (IFX) or azathioprine (AZA) withdrawal in pediatric patients with CD on combination therapy. Pediatric patients with moderate-to-severe CD receiving combination therapy were analyzed retrospectively and factors associated with clinical relapse were investigated. Discontinuation of IFX or AZA was performed in patients who sustained clinical remission (CR) for at least two years and achieved deep remission. A total of 75 patients were included. Forty-four patients (58.7%) continued with combination therapy and 31 patients (41.3%) discontinued AZA or IFX (AZA withdrawal 10, IFX withdrawal 15, both withdrawal 6). Cox proportional-hazards regression and statistical internal validation identified three factors associated with clinical relapse: IFX cessation (hazard ratio; HR 2.982, P = 0.0081), IFX TLs during maintenance therapy (HR 0.581, P = 0.003), 6-thioguanine nucleotide (6-TGN) level (HR 0.978, P < 0.001). However, AZA cessation was not associated with clinical relapse (P = 0.9021). Even when applied in pediatric patients who met stringent criteria, IFX cessation increased the relapse risk. However, withdrawal of AZA could be contemplated in pediatric patients with CD who have sustained CR for at least 2 years and achieved deep remission.
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Affiliation(s)
- Tae Jong Jeong
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Sil Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yiyoung Kwon
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seonwoo Kim
- Statistics and Data Center, Samsung Medical Center, Seoul, Korea
| | - Sang Won Seo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Neuroscience Center, Samsung Medical Center, Seoul, Korea.,Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Mi Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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11
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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: 10] [Impact Index Per Article: 2.5] [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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12
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Hashash JG, Fadel CGA, Rimmani HH, Sharara AI. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn's disease and ulcerative colitis. Ann Gastroenterol 2021; 34:612-624. [PMID: 34475731 PMCID: PMC8375659 DOI: 10.20524/aog.2021.0645] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/12/2021] [Indexed: 12/19/2022] Open
Abstract
Despite current guidelines, the optimal treatment of patients with inflammatory bowel disease (IBD) remains challenging. The available medications are not without risk and there is not a single correct treatment regimen for every patient. Personalizing treatment and selecting the most appropriate therapy is crucial for optimal response, remission, quality of life, and healthcare utilization. Biologics, especially anti-tumor necrosis factor-α medications, are widely used in the induction and maintenance of disease remission in patients with IBD. Similarly, immunomodulators, including thiopurines and methotrexate, are traditionally popular for the maintenance of remission. In this manuscript, we review the use of biologic monotherapy vs. combination therapy with immunomodulators for the treatment of ulcerative colitis and Crohn's disease. We examine overall remission, immunogenicity and adverse effects, mainly serious infections and malignancy, in an effort to help guide treatment decisions and weigh the risks and benefits of biologic monotherapy vs. combination therapy.
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Affiliation(s)
- Jana G. Hashash
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Carla G. Abou Fadel
- Division of Gastroenterology, Bellevue Medical Center, Mansourieh (Carla G. Abou Fadel), Lebanon
| | - Hussein H. Rimmani
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Ala I. Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
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13
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Kobayashi T. Stopping Anti-TNF in CD Remitters: Cons. Inflamm Intest Dis 2021; 7:59-63. [DOI: 10.1159/000517961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/21/2021] [Indexed: 11/19/2022] Open
Abstract
Crohn’s disease may cause a life-long disease burden in many aspects due to its progressive nature. A large proportion of refractory patients have been benefiting from scheduled maintenance anti-TNF treatment; therefore, strategy to stop anti-TNF agents in Crohn’s disease is not widely conducted. There have been observational studies demonstrating that approximately half of the patients relapse within a year after discontinuation. Several factors have been suggested as potential predictors for relapse; however, a consensus has not been reached so far. Although most relapse can be rescued by the re-treatment with the same anti-TNF agent, a proportion of patients may result in progressive bowel damage and the need for surgery. Therefore, an attempt to stop anti-TNF is not recommended without careful discussion, even if they are in long-term remission.
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Gargallo-Puyuelo CJ, Laredo V, Gomollón F. Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era? Front Med (Lausanne) 2021; 8:681907. [PMID: 34336887 PMCID: PMC8322650 DOI: 10.3389/fmed.2021.681907] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/23/2021] [Indexed: 12/18/2022] Open
Abstract
Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.
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Affiliation(s)
| | - Viviana Laredo
- Department of Gastroenterology, University Clinic Hospital Lozano Blesa, Zaragoza, Spain
| | - Fernando Gomollón
- Department of Gastroenterology, University Clinic Hospital Lozano Blesa, Zaragoza, Spain.,Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Zaragoza, Spain.,Institute for Health Research Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas, Madrid, Spain
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15
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Lambrescak E, Vaysse T, Allez M, Ungar B, Gleizes A, Hacein-Bey S, Chowers Y, Roblin X, Kopylov U, Rachas A, Carbonnel F. Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2021; 45:101503. [PMID: 32893176 DOI: 10.1016/j.clinre.2020.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 06/02/2020] [Accepted: 07/10/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Patients who receive infliximab (IFX) combined with a thiopurine, for inflammatory bowel disease, have a better clinical response and less frequent immunization towards IFX than those treated with IFX alone. The benefits of combination therapy must be weighed against the risks of infection and cancer. We studied the association between the duration of combination therapy and the risk of treatment failure by two year from initiation. METHODS Participants had Crohn's disease or ulcerative colitis and were in clinical and biological remission, 6 months after initiation of combination therapy. The risk of subsequent treatment failure (i.e., undetectable trough IFX levels and/or clinical relapse followed by surgical treatment or switch of maintenance treatment) was estimated using Kaplan-Meier method and adjusted Hazard Ratios (aHRs), in patients whohadreceived 6 to 11 months vs. 12 months or more of combination therapy. We performed a similar analysis in which the follow-up was started at discontinuation of the immunosuppressant. RESULTS Among 139 patients (48% women; median age 31.1), with a median follow-up of 18.9 months, we observed 26 treatment failures (including 15 patients with undetectable trough IFX levels). After adjustment for gender and type of immunomodulator, a shorter duration of combination therapy was not associated with a higher risk of treatment failure (aHR=0.42; 95% confidence interval (95%CI): 0.13-1.40; p=0.16). When the follow-up was started at discontinuation of the immunosuppressant, a combination therapy of 6-11 months was associated with a numerically lower risk of treatment failure as compared with a longer combination therapy (HR=0.12; 95%CI: 0.01-1.05; p=0.055). CONCLUSION Our results do not show any benefit for continuation of combination therapy for more than 12 months after achieving clinical remission in IBD patients.
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Affiliation(s)
- Elsa Lambrescak
- Hôpital du Kremlin-Bicêtre, Service de Gastroentérologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Thibaut Vaysse
- Hôpital du Kremlin-Bicêtre, Service de Gastroentérologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Matthieu Allez
- Hôpital Saint Louis, Service de Gastroentérologie, APHP, Université Denis Diderot, 1 Avenue Claude, Vellefaux 75010, France
| | - Bella Ungar
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Ramat Gan, affiliated to Sackler Medical School, Tel Aviv University, Israel
| | - Aude Gleizes
- Hôpital du Kremlin-Bicêtre, Laboratoire d'immunologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Salima Hacein-Bey
- Hôpital du Kremlin-Bicêtre, Laboratoire d'immunologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Yehuda Chowers
- Gastroenterology Institute, Rambam Rambam Health Care Campus, Haifa, Israel
| | - Xavier Roblin
- CHU de Saint-Etienne, Hôpital Bellevue, Service d'hépato-gastro-entérologie, 25 Boulevard Pasteur, 42055 Saint-Etienne Cedex 2, France
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Ramat Gan, affiliated to Sackler Medical School, Tel Aviv University, Israel
| | - Antoine Rachas
- Hôpital du Kremlin-Bicêtre, Service de Santé Publique, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Franck Carbonnel
- Hôpital du Kremlin-Bicêtre, Service de Gastroentérologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
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16
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Shi JH, Luo L, Chen XL, Pan YP, Zhang Z, Fang H, Chen Y, Chen WD, Cao Q. Real-world cost-effectiveness associated with infliximab maintenance therapy for moderate to severe Crohn’s disease in China. World J Gastroenterol 2020; 26:6455-6474. [PMID: 33244205 PMCID: PMC7656205 DOI: 10.3748/wjg.v26.i41.6455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/05/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Infliximab was the first approved biologic treatment for moderate to severe Crohn’s disease (MS-CD) in China. However, the cost-effectiveness of infliximab maintenance therapy (IMT) for MS-CD relative to conventional maintenance therapy remained unclarified.
AIM To assess the cost-effectiveness of IMT for MS-CD in Chinese patients from the perspective of Chinese public insurance payer.
METHODS A cohort of MS-CD patients managed in a Chinese tertiary care hospital was created to compare IMT with conventional maintenance therapy (CMT) for clinical outcomes and direct medical costs over a 1-year observation time using conventional regression analyses. A decision-analytic model with the generated evidence was constructed to assess the cost-effectiveness of IMT relative to CMT using reimbursed medical costs.
RESULTS Based on the included 389 patients, IMT was associated with significantly higher disease remission chance [odds ratio: 4.060, P = 0.003], lower risk of developing new complications (odds ratio: 0.527, P = 0.010), higher utility value for quality of life (coefficient 0.822, P = 0.008), and lower total hospital costs related to disease management (coefficient -0.378, P = 0.008) than CMT. Base-case cost-effectiveness analysis estimated that IMT could cost Chinese health insurance payers ¥55260 to gain one quality-adjusted life year (QALY). The cost-effectiveness of IMT was mainly driven by the estimate of quality of life, treatment efficacy of maintenance therapy, mortality risk associated with active disease, and unit price of infliximab. The probability that IMT was cost-effective at a willingness-to-pay threshold of three times gross domestic product [2018 Chinese gross domestic product per capita (GDPPC)] was 86.4%.
CONCLUSION IMT significantly improved real-world health outcomes and cost the Chinese public health insurance payers less than one GDPPC to gain one QALY in Chinese MS-CD patients.
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Affiliation(s)
- Ji-Hao Shi
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Liang Luo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Xiao-Li Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yi-Peng Pan
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhou Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Hao Fang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Ying Chen
- Department of Project, Changsha Normin Health Technology Ltd, Changsha 410013, Hunan Province, China
| | - Wen-Dong Chen
- Department of HEOR, Normin Health Consulting Ltd, Toronto L5R 0E9, Ontario, Canada
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China
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17
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Hirten RP, Lakatos PL, Halfvarson J, Colombel JF. A User's Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2020; 18:1336-1345. [PMID: 31887444 DOI: 10.1016/j.cgh.2019.12.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 12/05/2019] [Accepted: 12/08/2019] [Indexed: 02/07/2023]
Abstract
De-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. This review evaluates the published literature regarding therapeutic de-escalation and provides a framework for physicians to apply this to clinical practice. Prospective trials are underway and planned, which should provide further insight into this treatment paradigm and better inform patient selection for this strategy.
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Affiliation(s)
- Robert P Hirten
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Peter L Lakatos
- Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada; 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jean Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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18
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Alinaghi F, Tekin HG, Burisch J, Wu JJ, Thyssen JP, Egeberg A. Global Prevalence and Bidirectional Association Between Psoriasis and Inflammatory Bowel Disease-A Systematic Review and Meta-analysis. J Crohns Colitis 2020; 14:351-360. [PMID: 31504363 DOI: 10.1093/ecco-jcc/jjz152] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Epidemiological studies have established an association between psoriasis and inflammatory bowel disease [IBD], i.e. ulcerative colitis [UC] and Crohn's disease [CD], but results are inconsistent. The aim of this study was therefore to quantify the prevalences and association between IBD and psoriasis. METHODS PubMed, Web of Science, and EMBASE were searched from database inception through April 2018 for studies reporting data on psoriasis among patients with IBD and vice versa. Meta-analysis was performed to estimate, respectively, the prevalences and association between IBD and psoriasis. Data extraction was according to the PRISMA guideline, and quality assessment was made using the Newcastle-Ottawa Scale. The main outcomes were the proportion of psoriasis patients with IBD and vice versa, as well as the association (odds ratio [OR]) of IBD in psoriasis and psoriasis in IBD, respectively. RESULTS Based on quantitative analysis of 93 studies, the prevalence of psoriasis in CD and in UC was 3.6% (95% confidence interval [CI] 3.1%-4.6%) and 2.8% [95% CI 2.0%-3.8%] respectively. The prevalence of CD and UC was 0.7% [95% CI 0.2%-1.3%] and 0.5% [95% CI 0.3%-0.8%], respectively, among patients with psoriasis. Presence of CD or UC was significantly associated with psoriasis, with OR 2.0 [95% CI 1.4-2.9] and OR 1.5 [95% CI 1.2-2.0], respectively. Presence of psoriasis was significantly associated with CD: OR 2.2 [95% CI 1.6-3.1] and with UC: OR 1.6 [95% CI 1.3-2.0]. CONCLUSIONS We found significant bidirectional associations between psoriasis and IBD, warranting increased awareness among clinicians in the diagnostic process, especially in children and adolescents with IBD. Last, this study showed an increased frequency of paradoxical psoriasis in patients treated with biologics.
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Affiliation(s)
- Farzad Alinaghi
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Hasan Göcker Tekin
- Department of Plastic Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Johan Burisch
- Gastro-unit, Hvidovre Hospital, University of Copenhagen, Hidovre, Denmark
| | - Jashin J Wu
- Department of Dermatology, Dermatology Research and Education Foundation, Irvine, CA, USA
| | - Jacob P Thyssen
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Egeberg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
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19
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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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20
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Infliximab therapy intensification upon loss of response: Is there an optimal trough level? Dig Liver Dis 2019; 51:1106-1111. [PMID: 30928420 DOI: 10.1016/j.dld.2019.02.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/13/2019] [Accepted: 02/24/2019] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Loss of response (LOR) to infliximab occurs in ∼30% of IBD patients. At time of LOR, lower infliximab-trough-levels (TL), in the absence of anti-drug-antibodies (ATI), have been associated with the need for therapy escalation. Nevertheless, few studies have examined the outcome of infliximab-therapy intensification, based on different TL. AIM To evaluate the impact of infliximab-TL on efficacy of therapy intensification (dose-elevation/interval-shortening). METHODS This was a retrospective observational study performed at two tertiary-centers between 2013-2017. Study population included IBD patients who underwent infliximab therapy escalation (dose elevation/interval shortening) due to clinical LOR. Patients with TL < 3 μg/ml or positive ATI were excluded. TL and clinical scores before intensification and after 6, 12 months were obtained prospectively. RESULTS Forty-eight IBD patients were included; 23(49%), and 29(60%) reached clinical remission by 6, 12 months before intensification. TL among patients in clinical remission were significantly lower than among those clinically active, both at 6 (p = 0.001, median TL 4.7,8.7 μg/ml, IQR 3.6-8.1, 5.9-16 μg/ml) and 12 months (p = 0.005, median TL 4.6,8.7 μg/ml, IQR 3.6-8, 5.3-16 μg/ml), respectively. CONCLUSIONS In IBD patients experiencing clinical LOR to infliximab in the absence of ATI, success of doubling the dose was inversely associated with baseline TL. Patients with baseline TL above 9 mcg/ml were very unlikely to reach clinical remission.
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21
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Sparrow MP, Melmed GY, Devlin S, Kozuch P, Raffals L, Loftus Jr EV, Rubin DT, Spiegel B, Baidoo L, Bressler B, Cheifetz A, Irving P, Jones J, Kaplan GG, Velayos F, Siegel CA. De‐escalating medical therapy in Crohn’s disease patients who are in deep remission: A RAND appropriateness panel. ACTA ACUST UNITED AC 2019. [DOI: 10.1002/ygh2.337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Miles P. Sparrow
- The BRIDGe Group
- The Alfred Hospital Melbourne Victoria Australia
| | - Gil Y. Melmed
- The BRIDGe Group
- Cedars‐Sinai Medical Center Los Angeles California
| | - Shane Devlin
- The BRIDGe Group
- University of Calgary Calgary Alberta Canada
| | - Patricia Kozuch
- The BRIDGe Group
- Jefferson University Philadelphia Pennsylvania
| | | | | | | | | | | | - Brian Bressler
- The BRIDGe Group
- University of British Columbia Vancouver British Columbia Canada
| | - Adam Cheifetz
- The BRIDGe Group
- Beth Israel Deaconess Medical Center Boston Massachusetts
| | - Peter Irving
- The BRIDGe Group
- Guy's and St. Thomas' Hospitals London UK
| | - Jennifer Jones
- The BRIDGe Group
- Dalhousie University Halifax Nova Scotia Canada
| | | | | | - Corey A. Siegel
- The BRIDGe Group
- Dartmouth‐Hitchcock IBD Center Lebanon New Hampshire
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22
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Sedano Muñoz R, Quera Pino R, Lubascher Correa J, Pizarro Jofré G, Simian Marín D. Evaluation of de-escalation of anti-TNF-α therapy in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:133-140. [PMID: 30595227 DOI: 10.1016/j.gastrohep.2018.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 10/15/2018] [Indexed: 06/09/2023]
Abstract
Anti-tumour necrosis factor α therapy in inflammatory bowel disease has been shown to be effective in clinical practice. After more than a decade using these therapies the question arises about whether there is an appropriate time to suspend these therapies, and how this should be done. This review aims to evaluate the current evidence on these topics concerning anti-tumour necrosis factor α therapies, and eventually identify conditions and subgroups of patients that could potentially be candidates for withdrawal.
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Affiliation(s)
- Rocío Sedano Muñoz
- Servicio de Gastroenterología, Hospital Clínico de la Universidad de Chile, Santiago, Chile.
| | - Rodrigo Quera Pino
- Programa Enfermedad Inflamatoria Intestinal, Clínica Las Condes, Santiago, Chile; Departamento de Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Jaime Lubascher Correa
- Programa Enfermedad Inflamatoria Intestinal, Clínica Las Condes, Santiago, Chile; Departamento de Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Gonzalo Pizarro Jofré
- Programa Enfermedad Inflamatoria Intestinal, Clínica Las Condes, Santiago, Chile; Departamento de Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Daniela Simian Marín
- Programa Enfermedad Inflamatoria Intestinal, Clínica Las Condes, Santiago, Chile; Sub-Dirección Académica, Clínica Las Condes, Santiago, Chile
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23
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Abstract
PURPOSE OF REVIEW Currently, inflammatory bowel disease treatment is based on immunomodulators (IM) and/or biologic as this strategy may prevent the development of irreversible damage. Nevertheless, long-term treatment may be associated with non-negligible side effects and with high costs, and therefore the question on whether therapy can be de-escalated is often posed in clinical practice. RECENT FINDINGS Recent studies have shown a predictable rate of relapse after stop biologic or IM therapy withdrawal. Overall, around 40-50% of patients will eventually relapse over the following year after drug withdrawal, and the rates will increase over time. Stratification of patients and therapeutic drug monitoring could be promising alternatives to guide therapeutic management. We reviewed the current evidence on de-escalation strategy and summarised the recent results on discontinuation and dose reduction. Nowadays, de-escalation strategy is still a case-by-case decision in highly selected patients.
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Affiliation(s)
- Catarina Frias Gomes
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
| | - Jean-Frédéric Colombel
- Medicine Department, Gastroenterology Division, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
| | - Joana Torres
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
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24
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Kim YS. [How to Optimally Use Currently Available Drugs in a Therapeutic Algorithm?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 71:74-80. [PMID: 29471604 DOI: 10.4166/kjg.2018.71.2.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Recently, the incidence and prevalence of inflammatory bowel disease (IBD) have been increasing in worldwide, especially in Asian area. IBD is a chronic and progressive disease eventually causing bowel damage. The advance in the treatment of IBD over the past several decades has been achieved with the development of biologics. Furthermore, goals for management of IBD have been evolving from symptom-based management to mucosal healing, which can reduce the surgery rate and hospitalization. To treat the patients with IBD properly, identification of risk factors of patients should be preceded. In addition, the knowledge of several drugs, which are available in current situation is essential. In this review, optimal therapeutic approach with drugs including 5-aminosalicylate, steroid, immunomodulators and anti-TNF antagonists is discussed.
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Affiliation(s)
- You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
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Day AS, Gulati AS, Patel N, Boyle B, Park KT, Saeed SA. The Role of Combination Therapy in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 66:361-368. [PMID: 29210919 DOI: 10.1097/mpg.0000000000001850] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The treatment goal for children suffering from inflammatory bowel disease has been evolving with biologic therapies like anti-tumor necrosis factor agents assuming a more central role in treatment of more aggressive and extensive phenotype. Earlier introduction of anti-tumor necrosis factor agents have shown to be more effective and may even alter the natural history of inflammatory bowel disease. Development of anti-drug antibodies, however, limits long-term usage and leads to dose adjustment in almost half of patients treated with these medications. One of the strategies to minimize the development of anti-drug antibodies has been concomitant use of immunomodulator medications, resulting in fewer infusion reactions and sustained trough levels, potentially lowering the need for dose adjustments. Balanced with these benefits of optimized dosing and likely more sustained response, however, is the concern about increased risk of complications, such as infections and malignancies. The current manuscript reviews the available pediatric literature regarding efficacy, safety, and side effect profile of combination (immunomodulator and biologics) therapy in pediatric Crohn disease and ulcerative colitis, with particular emphasis on cost constraints, and recommendations for selection of patients who would benefit most from combination therapy.
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Affiliation(s)
- Andrew S Day
- Department of Paediatrics, University of Otago (Christchurch), Christchurch, NZ
| | - Ajay S Gulati
- Department of Pediatrics, Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Nishaben Patel
- Division of Pediatric Gastroenterology/Nutrition, Golisano Children's Hospital, Rochester, NY
| | - Brendan Boyle
- Division of Gastroenterology, Hepatology, Nutrition, Nationwide Children's Hospital, Columbus, OH
| | - K T Park
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Stanford University School of Medicine, Palo Alto, CA
| | - Shehzad A Saeed
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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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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Abstract
Despite the proven efficacy of biological drugs for inflammatory bowel disease, these therapies are costly and do carry some risks, providing incentive for exploring strategies to discontinue therapy in patients with prolonged remission. We presently review multiple cohort studies indicating the overall risk of relapse after stopping an anti-tumor necrosis factor (TNF) in inflammatory bowel disease patients is roughly 40% at 12 months after therapy cessation. Despite methodological differences across studies, it appears that patients without deep remission (ie, patients with endoscopic or biomarker evidence of inflammation) are at increased risk of relapse after stopping anti-TNF, as are those with high-adequate levels of anti-TNF before stopping. In patients who relapse after anti-TNF cessation, retreatment with the same biological seems to reinduce clinical response in most patients. Immunological reasons responsible for this high success rate for retreatment are elucidated, but resorting to retreatment also implies a small but finite risk of a severe flare leading to surgery, which should be borne in mind. Thus, stopping attempts should probably be reserved for patients with low risk for severe outcome should a relapse occur. Proactive endoscopic monitoring after drug cessation is imperative to reduce these risks. The recently introduced concept of treatment-cycles is discussed, along with a pragmatic algorithm of decision tree for therapy discontinuation in the selected appropriate patients.
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Risk Factors for Rescue Therapy in Crohn's Patients Maintained on Infliximab After Withdrawal of the Immunomodulator: A Long-Term Follow-Up. Dig Dis Sci 2017; 62:3131-3137. [PMID: 28986660 DOI: 10.1007/s10620-017-4771-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/16/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Usefulness of thiopurine and scheduled infliximab combination therapy in non-immunomodulator (IM)-naïve Crohn's disease (CD) patients and the optimal length of dual therapy are still debated. AIMS To determine proportion of patients developing disease flare requiring rescue therapy and risk factors associated with disease flare after de-escalation of IM from combination therapy. METHODS Adult CD patients in clinical remission on combination therapy were identified from a large single-center database between 2002 and 2009. Patients who had their IM stopped in the absence of adverse events were included. Association between clinical and demographic variables and time until rescue therapy was analyzed using Cox-proportional hazard models. RESULTS Forty-three CD patients on combination therapy in clinical remission at time of IM de-escalation were identified and followed up for a median duration of 61.6 months (range 5.4-129.5). Median duration of remission on combination therapy prior to IM de-escalation was 12.0 months (range 4-74). Thirty-one patients (72.1%) required rescue therapy during follow-up. On multivariable analysis, age at diagnosis < 16 years versus > 40 years (HR 4.55, 95% CI 1.18-17.62, p = 0.028), using methotrexate instead of azathioprine in combination with infliximab (HR 3.37, 95% CI 1.14, 9.96, p = 0.028), and duration of combination therapy < 6 months (HR 5.68, 95% CI 1.58, 20.36, p = 0.007) increased risk for rescue therapy. CONCLUSIONS A large proportion of CD patients on combination therapy experienced a flare following IM withdrawal. Young age at diagnosis, short duration of combination therapy, and methotrexate use were independent predictors of the need for rescue therapy.
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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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Roblin X, Boschetti G, Williet N, Nancey S, Marotte H, Berger A, Phelip JM, Peyrin-Biroulet L, Colombel JF, Del Tedesco E, Paul S, Flourie B. Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial. Aliment Pharmacol Ther 2017; 46:142-149. [PMID: 28449228 DOI: 10.1111/apt.14106] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/09/2017] [Accepted: 03/26/2017] [Indexed: 01/14/2023]
Abstract
BACKGROUND Infliximab (IFX) combined with azathioprine (AZA) is more effective than IFX monotherapy in inflammatory bowel disease (IBD). AIM To identify the AZA optimal dose that is required for efficacy when receiving combination therapy. METHODS Patients with IBD in durable remission on combination therapy were enrolled in a 1-year, open-label, prospective trial after randomisation into three groups: AZA steady (2-2.5 mg/kg/day, n=28) vs AZA down (dose was halved 1-1.25 mg/kg/day, n=27) vs AZA stopped (n=26). Primary endpoint was failure defined as occurrence of a clinical relapse and/or any change in IBD therapy. RESULTS Eighty-one patients were included. Five (17.9%), 3 (11.1%), and 8 (30.8%) patients experienced failure at 1 year in groups AZA steady, AZA down and AZA stopped, respectively (P=.1 across the groups). The median trough levels of IFX at inclusion were close to those measured at the end of follow-up in group AZA steady (3.65 vs 3.45 μg/mL, P=.9) and in group AZA down (3.95 vs 3.60 μg/mL, P=.5), whereas these levels dropped from 4.25 to 2.15 μg/mL (P=.02) in group AZA stopped. Four (14.3%), four (14.8%) and 11 (42.3%) patients experienced an unfavourable evolution of IFX pharmacokinetics in groups AZA steady, AZA down and AZA stopped, respectively. A threshold of 6-TGN <105 pmoles/8.108 RBC was associated with an unfavourable evolution of IFX pharmacokinetics. CONCLUSIONS Under combination therapy, AZA dose reduction, but not withdrawal, appears to be as effective as continuation of AZA at full dose.
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Affiliation(s)
- X Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - G Boschetti
- Department of Gastroenterology, Hospices Civils de Lyon, INSERM U1111, Lyon, France
| | - N Williet
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - S Nancey
- Department of Gastroenterology, Hospices Civils de Lyon, INSERM U1111, Lyon, France
| | - H Marotte
- Department of Rheumatology, University Hospital of Saint Etienne, Saint Etienne, France
| | - A Berger
- Department of Immunology, CIC1408, GIMAP EA3064, University Hospital of Saint Etienne, Saint Etienne, France
| | - J M Phelip
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - L Peyrin-Biroulet
- Department of Gastroenterology, University Hospital of Nancy, Nancy, France
| | - J F Colombel
- Division of Gastroenterology, Inflammatory Bowel Disease Center, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA
| | - E Del Tedesco
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - S Paul
- Department of Immunology, CIC1408, GIMAP EA3064, University Hospital of Saint Etienne, Saint Etienne, France
| | - B Flourie
- Department of Gastroenterology, Hospices Civils de Lyon, INSERM U1111, Lyon, France
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Sturm A, Maaser C, Mendall M, Karagiannis D, Karatzas P, Ipenburg N, Sebastian S, Rizzello F, Limdi J, Katsanos K, Schmidt C, Jeuring S, Colombo F, Gionchetti P. European Crohn's and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis 2017; 11:263-273. [PMID: 27797918 DOI: 10.1093/ecco-jcc/jjw188] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/17/2016] [Accepted: 10/18/2016] [Indexed: 12/12/2022]
Abstract
This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focuses on the epidemiology, pathophysiology, diagnosis, management and outcome of the two most common forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, in elderly patients. The objective was to reach expert consensus to provide evidence-based guidance for clinical practice.
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Affiliation(s)
- Andreas Sturm
- Department of Gastroenterology, DRK Kliniken Berlin I Westend. Akademisches Lehrkrankenhaus der Charite, Spandauer Damm 130, 14050 Berlin, Germany
| | - Christian Maaser
- Outpatients Department of Gastroenterology and Department of Geriatrics, Hospital Lüneburg, Bögelstraße 1, 21339 Lüneburg, Germany
| | - Michael Mendall
- Croydon University Hospital, Mayday Road, CR4 7YE Thornton Heath; & St George's Medical School, Cranmer Terrace SW17 ORE, UK
| | - Dimitrios Karagiannis
- Department of Gastroenterology, Iatriko Kentro Athinon, Dervenakion St. 3, 14572 Athens, Greece
| | - Pantelis Karatzas
- Department of Gastroenterology, Evangelismos Hospital, 45-47 Ypsilantou Street, 10676 Athens, Greece
| | - Nienke Ipenburg
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Shaji Sebastian
- IBD Unit, Hull & East Yorkshire NHS Trust, Anlaby Road, Hull HU3 2JZ, UK
| | - Fernando Rizzello
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
| | - Jimmy Limdi
- Department of Gastroenterology, Pennine Acute Hospitals NHS Trust, Manchester M8 5RB, Institute of Inflammation and Repair, Manchester Academic Health Sciences, University of Manchester, UK
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, PO Box 1186, 45110 Ioannina, Greece
| | - Carsten Schmidt
- Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
| | - Steven Jeuring
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC), PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Francesco Colombo
- Dipartimento di Area Chirurgica, Ospedale "Luigi Sacco"- Polo Universitario, ASST Fatebenefratelli Sacco, Milano, Italy
| | - Paolo Gionchetti
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
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Mantzaris GJ. Thiopurines and Methotrexate Use in IBD Patients in a Biologic Era. ACTA ACUST UNITED AC 2017; 15:84-104. [DOI: 10.1007/s11938-017-0128-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Coskun M, Steenholdt C, de Boer NK, Nielsen OH. Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease. Clin Pharmacokinet 2016; 55:257-74. [PMID: 26255287 DOI: 10.1007/s40262-015-0316-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.
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Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. .,Department of Biology and Biotech Research and Innovation Centre (BRIC), The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.
| | - Casper Steenholdt
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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The Efficacy of Infliximab Monotherapy versus Infliximab-Azathioprine Sequential Treatment in Crohn's Disease: Experience from a Tertiary Medical Center in China. BIOMED RESEARCH INTERNATIONAL 2016; 2016:8648307. [PMID: 27896276 PMCID: PMC5118525 DOI: 10.1155/2016/8648307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 10/01/2016] [Accepted: 10/09/2016] [Indexed: 02/08/2023]
Abstract
Objective. To evaluate the efficacy of infliximab (IFX) monotherapy versus infliximab-azathioprine sequential treatment in Crohn's disease (CD) patients. Methods. Patients newly diagnosed with CD using IFX as induction therapy were enrolled. After 6 times of IFX infusions, they were divided into IFX monotherapy group and IFX-AZA sequential therapy group. Clinical remission rates were assessed at weeks 57, 84, 111, and 138 while endoscopic remission rates were assessed at weeks 84 and 138 to evaluate the efficacy of these two groups. Results. A total of seventy-nine patients had accomplished 138-week follow-up. At weeks 84 and 138, the deep remission rate (18/22 and 17/22) of IFX monotherapy group was significantly higher compared to IFX-AZA sequential therapy group (26/57 and 21/57) (P = 0.004 and 0.001, resp.). Similar findings were found in complete endoscopic remission rate. The clinical remission rates of IFX monotherapy group were similar to that of IFX-AZA sequential therapy group (P > 0.05). At weeks 84 and 138, the endoscopic remission rate and the endoscopic improvement rate between these two groups displayed no significant difference (P > 0.05). Conclusion. IFX monotherapy provides higher deep remission rate compared with IFX-AZA sequential therapy in two-year maintenance therapy. For patients who could not receive prolonged IFX therapy, IFX-AZA sequential therapy is acceptable, though long-term efficacy remains to be seen.
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35
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Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2733-2747. [PMID: 27760078 DOI: 10.1097/mib.0000000000000923] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.
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González-Lama Y, Gisbert JP. Monitoring thiopurine metabolites in inflammatory bowel disease. Frontline Gastroenterol 2016; 7:301-307. [PMID: 28839871 PMCID: PMC5369498 DOI: 10.1136/flgastro-2015-100681] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 03/09/2016] [Accepted: 03/16/2016] [Indexed: 02/04/2023] Open
Abstract
Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease.
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Affiliation(s)
- Yago González-Lama
- Gastroenterology and Hepatology Department, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Madrid, Spain
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Pouillon L, Bossuyt P, Peyrin-Biroulet L. Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease. Expert Opin Biol Ther 2016; 16:1277-90. [PMID: 27329436 DOI: 10.1080/14712598.2016.1203897] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD). AREAS COVERED Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized. EXPERT OPINION Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.
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Affiliation(s)
- Lieven Pouillon
- a Department of Hepato-Gastroenterology , University Hospitals Leuven, Uz Gasthuisberg , Leuven , Belgium
| | - Peter Bossuyt
- b Imelda GI Clinical Research Centre , Imeldaziekenhuis Bonheiden , Bonheiden , Belgium
| | - Laurent Peyrin-Biroulet
- c Inserm U954 and Department of Gastroenterology , Nancy University Hospital, Université de Lorraine , Vandœuvre-lès-Nancy , France
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Ampuero J, Rojas-Feria M, Castro-Fernández M, Millán-Lorenzo M, Guerrero-Jiménez P, Romero-Gómez M. Remission maintained by monotherapy after biological + immunosuppressive combination for Crohn's disease in clinical practice. J Gastroenterol Hepatol 2016; 31:112-8. [PMID: 26173493 DOI: 10.1111/jgh.13039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 04/27/2015] [Accepted: 06/25/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM The optimal time to withdraw combined biological + immunosuppressive therapy in Crohn's disease is debated. Following remission of 6 months with the combined therapy, we assessed the efficacy of monotherapy in maintaining remission. METHODS Crohn's disease patients (n = 75) were retrospectively selected from clinical records for having achieved remission within 6 months of receiving combined biological + immunosuppressive therapy. Treatment continued for a further year with one or the other of the combination drugs withdrawn. Clinical remission was defined as Crohn's Disease Activity Index (CDAI) < 150 and endoscopic remission as CDAI < 150 + absence of mucosal lesions + no signs of active inflammation on ileocolonoscopy. Crohn's disease relapse was defined as CDAI > 250. RESULTS Twenty-eight percent (21/75) patients were relapsers. Withdrawal of biological therapy was more frequent than immunosuppressive (73.3% vs 26.7%) with no significant differences in relapse rates (30.9% vs 20%; P = 0.401). Endoscopic remission was more accurate than clinical remission (relapse rates: 10.5% vs 33.9%; P = 0.05). C-reactive-protein was higher in relapsers (19.2 ± 23.7 mg/L vs 2.5 ± 4.7 mg/L; P = 0.009). Multivariate analysis indicated C-reactive protein > 5 mg/L (odds ratios [OR]: 30.12; 95% confidence intervals [95% CI]: 5.91-153.38; P = 0.0001) and younger age at diagnosis (OR: 1.10; 95% CI: 1.01-1.19; P = .047) as independent factors predicting relapse. There was a strong trend toward a protective effect of endoscopic remission (OR: 0.17; 95% CI: 0.02-1.22; P = 0.077). CONCLUSION A subgroup of Crohn's disease patients treated with combination therapy can be identified (C-reactive protein < 5 mg/L, endoscopic remission, and older age at Crohn's disease diagnosis) who would continue in remission despite cessation of the biological (expensive) component of the combination therapy.
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Affiliation(s)
- Javier Ampuero
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
| | - María Rojas-Feria
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
| | - Manuel Castro-Fernández
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
| | - Marina Millán-Lorenzo
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
| | - Pedro Guerrero-Jiménez
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
| | - Manuel Romero-Gómez
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
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Sharifi A, Hosseinzadeh-Attar MJ, Vahedi H, Nedjat S. A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients. Saudi J Gastroenterol 2016; 22:316-23. [PMID: 27488327 PMCID: PMC4991203 DOI: 10.4103/1319-3767.187606] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory condition and includes Crohn's disease (CD) and ulcerative colitis (UC). It has been proposed that Vitamin D supplementation may have a beneficial role in IBD. AIM To characterize the effects of Vitamin D on cathelicidin (hCAP/LL37) gene expression, ESR, and serum hs-CRP levels. MATERIALS AND METHODS Ninety UC patients on remission were randomized to receive 300,000 IU intramuscular Vitamin D or 1 mL normal saline as placebo, respectively. Before and 90 days after intervention, serum levels of 25 (OH)-Vitamin D3, PTH, Calcium, ESR, and hs-CRP were measured. Cathelicidin gene expression was also quantified using qRT-PCR. RESULTS Baseline serum 25-OH-Vitamin D3 levels were not different between the two groups and after intervention, increased only in Vitamin D group (P < 0.001). Hs-CRP levels were lower in Vitamin D group after intervention (Before: 3.43 ± 3.47 vs 3.86 ± 3.55 mg/L, P = 0.56; after: 2.31 ± 2.25 vs 3.90 ± 3.97 mg/L, P= 0.023). ESR decreased significantly in Vitamin D group (Before: 12.4 ± 6.1 vs 12.1 ± 5.3 mm/h, P= 0.77; after: 6.7 ± 4.5 vs 11.4 ± 5.5 mm/h, P< 0.001). The mean fold change in hCAP18 gene expression in Vitamin D group was significantly higher than placebo group. (Mean ± SD: 3.13 ± 2.56 vs 1.09 ± 0.56; median ± interquartile range: 2.17 ± 3.81 vs 0.87 ± 0.53, P< 0.001). CONCLUSION Decreases in ESR and hs-CRP levels and increase in LL37 gene expression support the hypothesis that Vitamin D supplementation may have a beneficial role in UC patients.
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Affiliation(s)
- Amrollah Sharifi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Hosseinzadeh-Attar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran,Address for correspondence: Dr. Mohammad Javad Hosseinzadeh-Attar, No: 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran. E-mail:
| | - Homayoon Vahedi
- Digestive Disease Research Center, Digestive Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saharnaz Nedjat
- Department of Epidemiology and Biostatistics, School of Public Health, Knowledge Utilization Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Torres J, Boyapati RK, Kennedy NA, Louis E, Colombel JF, Satsangi J. Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology 2015; 149:1716-30. [PMID: 26381892 DOI: 10.1053/j.gastro.2015.08.055] [Citation(s) in RCA: 166] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/10/2015] [Accepted: 08/13/2015] [Indexed: 12/14/2022]
Abstract
Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.
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Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Ray K Boyapati
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.
| | - Nicholas A Kennedy
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland
| | - Edouard Louis
- Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jack Satsangi
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland
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Ward MG, Irving PM, Sparrow MP. How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease? World J Gastroenterol 2015; 21:11331-11342. [PMID: 26525434 PMCID: PMC4616209 DOI: 10.3748/wjg.v21.i40.11331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/14/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.
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Abstract
Crohn's disease (CD) is a chronic, persistent, and destructive disorder with different forms of clinical behavior and the disease appears to be progressive over the long term. Providing greater levels of mucosal healing and resolution of clinical symptoms may modify the course of CD. This will often necessitate long-term therapy with immunosuppressant or biological therapies. Both these classes of drugs have side-effects and the latter are also very expensive. Identification of a subgroup of patients with a low risk of relapse and validation of the relevant predictors in various cohort studies are the key points to be able to cease immunosuppressant and/or biological therapy in patients with CD in stable remission. The individual parameters 'mucosal healing', 'deep remission', 'fecal calprotectin', and 'C-reactive protein' or various combinations of these parameters seem to be promising tools for predicting successful withdrawal of maintenance therapy.
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Gordon JP, McEwan PC, Maguire A, Sugrue DM, Puelles J. Characterizing unmet medical need and the potential role of new biologic treatment options in patients with ulcerative colitis and Crohn's disease: a systematic review and clinician surveys. Eur J Gastroenterol Hepatol 2015; 27:804-12. [PMID: 25933126 PMCID: PMC4892747 DOI: 10.1097/meg.0000000000000378] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/24/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Comparative outcomes of patients with ulcerative colitis (UC) and Crohn's disease (CD) prescribed a biologic therapy are inconclusive. The aim of this research was to characterize the degree of unmet medical need in patients with UC or CD and to identify the potential role for new therapies. METHODS A systematic literature review was undertaken of studies reporting outcomes associated with the use of existing biologic therapies in patients with UC or CD, focusing on the nature and rate of treatment failure. To complement the systematic review, contemporaneous data were obtained from a survey of practising gastroenterologists in the UK and France. Data were qualitatively combined in a narrative framework to evaluate the degree of unmet medical need among patients with UC or CD. RESULTS Studies identified in the systematic review (n = 120) were heterogeneous, particularly with respect to the definitions of treatment failure; estimates of treatment failure were high but uncertain. On the basis of standardized definitions, estimates of treatment failure provided by clinicians (n = 102) were high, and they were higher for second-line treatment failure (primary: ≤ 37%; secondary: ≤ 41%) compared with first-line treatment failure (primary: ≤ 26%; secondary: ≤ 28%). The majority of the systematic review and survey data were reflective of outcomes with infliximab and adalimumab. CONCLUSION High treatment failure rates associated with existing biologics, identified by the review and clinician surveys, indicate a need for other biologic treatment options to improve the management and outcomes for people with UC and CD. Outcomes associated with existing and new biologic treatments should be investigated in head-to-head randomized trials in the context of their likely uses in clinical practice.
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Affiliation(s)
- Jason P. Gordon
- Health Economics and Outcomes Research Ltd, Monmouth
- University of Adelaide, Department of Public Health, Adelaide, Australia
| | - Phil C. McEwan
- Health Economics and Outcomes Research Ltd, Monmouth
- Swansea Centre for Health Economics, Swansea University, Wales
| | | | | | - Jorge Puelles
- Takeda Pharmaceuticals, Takeda Development Centre, London, UK
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Yarur AJ, Kubiliun MJ, Czul F, Sussman DA, Quintero MA, Jain A, Drake KA, Hauenstein SI, Lockton S, Deshpande AR, Barkin JS, Singh S, Abreu MT. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin Gastroenterol Hepatol 2015; 13:1118-24.e3. [PMID: 25562796 DOI: 10.1016/j.cgh.2014.12.026] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 11/11/2014] [Accepted: 12/10/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01). CONCLUSIONS Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.
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Affiliation(s)
- Andres J Yarur
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | | | - Frank Czul
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Daniel A Sussman
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Maria A Quintero
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Anjali Jain
- Prometheus Laboratories, San Diego, California
| | | | | | | | - Amar R Deshpande
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Jamie S Barkin
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | | | - Maria T Abreu
- Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida.
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Ha C, Mathur J, Kornbluth A. Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9:497-505. [PMID: 25600263 DOI: 10.1586/17474124.2015.983079] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The anti-tumor necrosis factor-α (TNF) antibodies have revolutionized the management of ulcerative colitis and Crohn's disease. The development of assays to allow for the measurements of serum drug levels and anti-drug antibodies have provided a more objective means of therapeutic decision making, particularly among patients losing response to treatment. Additionally, more evidence is emerging that indicates the relationship between drug levels and response to therapy including clinical response, mucosal healing and sustained remission. The use of combination therapies of the anti-TNF agents and the thiopurine immunosuppressants may also decrease immunogenicity to the anti-TNF agents and potentiate response to therapy. With more evidence emerging evidence of the importance of therapeutic drug levels and anti-drug antibodies, clinicians may be able to better optimize the current arsenal of inflammatory bowel disease therapeutics to achieve greater rates of durable remission and improved quality of life.
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Affiliation(s)
- Christina Ha
- Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
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Filippi J, Laharie D, Michiels C, Flamand M, Bouguen G, Nancey S, Presles E, Paul S, Schneider S, Hébuterne X, Roblin X. Efficacy of sustained combination therapy for at least 6 months with thiopurines and infliximab in patients with ulcerative colitis in clinical remission: a retrospective multicenter French experience. J Crohns Colitis 2015; 9:252-8. [PMID: 25588386 DOI: 10.1093/ecco-jcc/jjv001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Long-term benefits of combination therapy (combotherapy) with infliximab (IFX) and azathioprine (AZA) have been less studied in ulcerative colitis (UC) than in Crohn's disease. The aim of the present study was to determine UC disease activity in patients who received at least 6 months of combotherapy, and whether cotreatment for more than 6 months was useful in these patients. METHODS A retrospective multicenter study was conducted in seven French academic centers from January 2010 to September 2012, including all UC patients having received at least 6 months of combotherapy in prolonged remission off steroids. During the follow-up period, which was divided into trimesters, scheduled IFX was continued as maintenance and AZA could be withdrawn. Assessment of UC activity by trimester was based on the following events: disease relapse defined by clinical relapse requiring a change of treatment, IFX failure, and colectomy. RESULTS Eighty-two patients were included (mean age 38 years; male:female ratio 1:1) and followed up for a median of 22.3±14.0 months. Comparing 393 trimesters of combotherapy with 282 trimesters of IFX alone, fewer clinical relapses were observed with combotherapy (p = 0.049). Similar results were observed for IFX failure (p = 0.048). No difference was observed for colectomy. Duration of combotherapy longer than 9 months was inversely associated with clinical relapse (hazard ratio = 0.32 [95% confidence interval 0.15-0.70]). CONCLUSIONS UC patients treated with combotherapy should maintain IFX and AZA for at least 9 months. Further studies are required to determine the optimal duration of combotherapy before stopping AZA in this situation.
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Affiliation(s)
- J Filippi
- Gastroenterology, University Hospital of Nice, Nice, France
| | - D Laharie
- Gastroenterology, University Hospital of Bordeaux, Bordeaux, France
| | - C Michiels
- Gastroenterology, University Hospital of Dijon, Dijon, France
| | - M Flamand
- Gastroenterology, University Hospital of Nantes, Nantes, France
| | - G Bouguen
- Gastroenterology, University Hospital of Rennes, Rennes, France
| | - S Nancey
- Gastroenterology, University Hospital of Lyon Sud, Lyon, France
| | - E Presles
- Gastroenterology and Clinic Investigation Center, University Hospital of Saint Etienne, Saint Etienne, France
| | - S Paul
- Gastroenterology, University Hospital of Nice, Nice, France
| | - S Schneider
- Gastroenterology, University Hospital of Nice, Nice, France
| | - X Hébuterne
- Gastroenterology, University Hospital of Nice, Nice, France
| | - X Roblin
- Gastroenterology and Clinic Investigation Center, University Hospital of Saint Etienne, Saint Etienne, France
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Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD. Inflamm Bowel Dis 2015; 21:307-14. [PMID: 25569737 PMCID: PMC5279914 DOI: 10.1097/mib.0000000000000284] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited. METHODS We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded. RESULTS Assays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohn's disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range [1.1-4.3]) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 μg/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohn's disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007). CONCLUSIONS ATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.
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Vavricka SR, Radivojevic S, Manser CN, Frei P, Burri E, Fried M, Schoepfer A, Peyrin-Biroulet L, Michetti P, Rogler G, Biedermann L. Addressing current treatment challenges in Crohn's disease in real life: a physician's survey. Dig Liver Dis 2014; 46:1066-71. [PMID: 25169961 DOI: 10.1016/j.dld.2014.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation. AIMS To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics. METHODS A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland (n=318). RESULTS In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%). CONCLUSIONS Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment.
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Affiliation(s)
- Stephan R Vavricka
- Division of Gastroenterology & Hepatology, Triemli Hospital, Zurich, Switzerland
| | - Sanja Radivojevic
- Division of Gastroenterology & Hepatology, Triemli Hospital, Zurich, Switzerland
| | - Christine N Manser
- Division of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Pascal Frei
- Division of Gastroenterology & Hepatology, Seespital Horgen, Horgen, Switzerland
| | - Emanuel Burri
- Division of Gastroenterology & Hepatology, Medical University Hospital Liestal, Liestal, Switzerland
| | - Michael Fried
- Division of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Alain Schoepfer
- Division of Gastroenterology & Hepatology, University Hospital Lausanne, Lausanne, Switzerland
| | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-lès-Nancy, France
| | - Pierre Michetti
- Clinic de la source, Gastroenterology, Lausanne, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Division of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland.
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Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, Amil Dias J, Barabino A, Braegger CP, Bronsky J, Buderus S, Martín-de-Carpi J, De Ridder L, Fagerberg UL, Hugot JP, Kierkus J, Kolacek S, Koletzko S, Lionetti P, Miele E, Navas López VM, Paerregaard A, Russell RK, Serban DE, Shaoul R, Van Rheenen P, Veereman G, Weiss B, Wilson D, Dignass A, Eliakim A, Winter H, Turner D. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014; 8:1179-1207. [PMID: 24909831 DOI: 10.1016/j.crohns.2014.04.005] [Citation(s) in RCA: 838] [Impact Index Per Article: 76.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 04/14/2014] [Accepted: 04/14/2014] [Indexed: 02/07/2023]
Abstract
Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.
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Affiliation(s)
- F M Ruemmele
- Department of Paediatric Gastroenterology, APHP Hôpital Necker Enfants Malades, 149 Rue de Sèvres 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 2 Rue de l'École de Médecine, 75006 Paris, France; INSERM U989, Institut IMAGINE, 24 Bd Montparnasse, 75015 Paris, France.
| | - G Veres
- Department of Paediatrics I, Semmelweis University, Bókay János str. 53, 1083 Budapest, Hungary
| | - K L Kolho
- Department of Gastroenterology, Helsinki University Hospital for Children and Adolescents, Stenbäckinkatu 11, P.O. Box 281, 00290 Helsinki, Finland
| | - A Griffiths
- Department of Paediatrics, Hospital for Sick Children, University of Toronto, 555 University Avenue, M5G 1X8 Toronto, ON, Canada
| | - A Levine
- Paediatric Gastroenterology and Nutrition Unit, Tel Aviv University, Edith Wolfson Medical Center, 62 HaLohamim Street, 58100 Holon, Israel
| | - J C Escher
- Department of Paediatric Gastroenterology, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, Netherlands
| | - J Amil Dias
- Unit of Paediatric Gastroenterology, Hospital S. João, A Hernani Monteiro, 4202-451, Porto, Portugal
| | - A Barabino
- Gastroenterology and Endoscopy Unit, Istituto G. Gaslini, Via G. Gaslini 5, 16148 Genoa, Italy
| | - C P Braegger
- Division of Gastroenterology and Nutrition, and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - J Bronsky
- Department of Pediatrics, University Hospital Motol, Uvalu 84, 150 06 Prague, Czech Republic
| | - S Buderus
- Department of Paediatrics, St. Marien Hospital, Robert-Koch-Str.1, 53115 Bonn, Germany
| | - J Martín-de-Carpi
- Department of Paediatric Gastroenterolgoy, Hepatology and Nutrition, Hospital Sant Joan de Déu, Paseo Sant Joan de Déu 2, 08950 Barcelona, Spain
| | - L De Ridder
- Department of Paediatric Gastroenterology, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, Netherlands
| | - U L Fagerberg
- Department of Pediatrics, Centre for Clinical Research, Entrance 29, Västmanland Hospital, 72189 Västerås/Karolinska Institutet, Stockholm, Sweden
| | - J P Hugot
- Department of Gastroenterology and Nutrition, Hopital Robert Debré, 48 Bd Sérurier, APHP, 75019 Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, 75018 Paris France
| | - J Kierkus
- Department of Gastroenterology, Hepatology and Feeding Disorders, Instytut Pomnik Centrum Zdrowia Dziecka, Ul. Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - S Kolacek
- Department of Paediatric Gastroenterology, Children's Hospital, University of Zagreb Medical School, Klaićeva 16, 10000 Zagreb, Croatia
| | - S Koletzko
- Department of Paediatric Gastroenterology, Dr. von Hauner Children's Hospital, Lindwurmstr. 4, 80337 Munich, Germany
| | - P Lionetti
- Department of Gastroenterology and Nutrition, Meyer Children's Hospital, Viale Gaetano Pieraccini 24, 50139 Florence, Italy
| | - E Miele
- Department of Translational Medical Science, Section of Paediatrics, University of Naples "Federico II", Via S. Pansini, 5, 80131 Naples, Italy
| | - V M Navas López
- Paediatric Gastroenterology and Nutrition Unit, Hospital Materno Infantil, Avda. Arroyo de los Ángeles s/n, 29009 Málaga, Spain
| | - A Paerregaard
- Department of Paediatrics 460, Hvidovre University Hospital, Kettegård Allé 30, 2650 Hvidovre, Denmark
| | - R K Russell
- Department of Paediatric Gastroenterology, Yorkhill Hospital, Dalnair Street, Glasgow G3 8SJ, United Kingdom
| | - D E Serban
- 2nd Department of Paediatrics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Emergency Children's Hospital, Crisan nr. 5, 400177 Cluj-Napoca, Romania
| | - R Shaoul
- Department of Pediatric Gastroenterology and Nutrition, Rambam Health Care Campus Rappaport Faculty Of Medicine, 6 Ha'alya Street, P.O. Box 9602, 31096 Haifa, Israel
| | - P Van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands
| | - G Veereman
- Department of Paediatric Gastroenterology and Nutrition, Children's University Hospital, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - B Weiss
- Paediatric Gastroenterology and Nutrition Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52625 Tel Hashomer, Israel
| | - D Wilson
- Child Life and Health, Paediatric Gastroenterology, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, United Kingdom
| | - A Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, 60431 Frankfurt/Main, Gemany
| | - A Eliakim
- 33-Gastroenterology, Sheba Medical Center, 52621 Tel Hashomer, Israel
| | - H Winter
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Mass General Hospital for Children, 175 Cambridge Street, 02114 Boston, United States
| | - D Turner
- Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
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Ananthakrishnan AN, Cheng SC, Cai T, Cagan A, Gainer VS, Szolovits P, Shaw SY, Churchill S, Karlson EW, Murphy SN, Kohane I, Liao KP. Serum inflammatory markers and risk of colorectal cancer in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014; 12:1342-8.e1. [PMID: 24407106 PMCID: PMC4085150 DOI: 10.1016/j.cgh.2013.12.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 12/21/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel diseases (IBDs) (Crohn's disease, ulcerative colitis) are at increased risk of colorectal cancer (CRC). Persistent inflammation is hypothesized to increase risk of CRC in patients with IBD; however, the few studies in this area have been restricted to cross-sectional assessments of histologic severity. No prior studies have examined association between C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) elevation and risk of CRC in an IBD cohort. METHODS From a multi-institutional validated IBD cohort, we identified all patients with at least one measured CRP or ESR value. Patients were stratified into quartiles of severity of inflammation on the basis of their median CRP or ESR value, and subsequent diagnosis of CRC was ascertained. Logistic regression adjusting for potential confounders was used to identify the independent association between CRP or ESR elevation and risk of CRC. RESULTS Our study included 3145 patients with at least 1 CRP value (CRP cohort) and 4008 with at least 1 ESR value (ESR cohort). Thirty-three patients in the CRP cohort and 102 patients in the ESR cohort developed CRC during a median follow-up of 5 years at a median age of 55 years. On multivariate analysis, there was a significant increase in risk of CRC across quartiles of CRP elevation (P(trend) = .017; odds ratio for quartile 4 vs quartile 1, 2.72; 95% confidence interval, 0.95-7.76). Similarly higher median ESR was also independently associated with risk of CRC across the quartiles (odds ratio, 2.06; 95% confidence interval, 1.14-3.74) (P(trend) = .007). CONCLUSIONS An elevated CRP or ESR is associated with increased risk of CRC in patients with IBD.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
| | - Su-Chun Cheng
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
| | - Tianxi Cai
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
| | - Andrew Cagan
- Research IS and Computing, Partners HealthCare, Charlestown, Massachusetts
| | - Vivian S Gainer
- Research IS and Computing, Partners HealthCare, Charlestown, Massachusetts
| | - Peter Szolovits
- Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Stanley Y Shaw
- Harvard Medical School, Boston, Massachusetts; Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts
| | - Susanne Churchill
- i2b2 National Center for Biomedical Computing, Brigham and Women's Hospital, Boston, Massachusetts
| | - Elizabeth W Karlson
- Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Shawn N Murphy
- Harvard Medical School, Boston, Massachusetts; Research IS and Computing, Partners HealthCare, Charlestown, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Isaac Kohane
- Harvard Medical School, Boston, Massachusetts; i2b2 National Center for Biomedical Computing, Brigham and Women's Hospital, Boston, Massachusetts; Children's Hospital Boston, Boston, Massachusetts
| | - Katherine P Liao
- Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts
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