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Salimi A, Sepehr A, Hejazifar N, Talebi M, Rohani M, Pourshafie MR. The Anti-Inflammatory Effect of a Probiotic Cocktail in Human Feces Induced-Mouse Model. Inflammation 2023; 46:2178-2192. [PMID: 37599322 DOI: 10.1007/s10753-023-01870-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 06/18/2023] [Accepted: 07/03/2023] [Indexed: 08/22/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract due to altered interaction between the immune system and the gut microbiota. The aim of this study was to investigate the role of a probiotic cocktail in modulating immune dysregulation induced in mice. Mice were divided into 5 groups (n = 5/group), and inflammation was induced in two separate groups by fecal microbiota transplantation (FMT) from the stool of human with IBD and dextran sulfate sodium (DSS). In the other two groups, the cocktail of Lactobacillus spp. and Bifidobacterium spp. (108CFU/kg/day) was administered daily for a total of 28days in addition to inducing inflammation. A group as a contcxsrol group received only water and food. The alteration of the selected genera of gut microbiota and the expression of some genes involved in the regulation of the inflammatory response were studied in the probiotic-treated and untreated groups by quantitative real-time PCR. The selected genera of gut microbiota of the FMT and DSS groups showed similar patterns on day 28 after each treatment. In the probiotic-treated groups, the population of the selected genera of gut microbiota normalized and the abundance of Firmicutes and Actinobacteria increased compared to the DSS and FMT groups. The expression of genes related to immune response and tight junctions was positively affected by the probiotic. Changes in the gut microbiota could influence the inflammatory status in the gut, and probiotics as a preventive or complementary treatment could improve the well-being of patients with inflammatory bowel disease symptoms.
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Affiliation(s)
- Afsaneh Salimi
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - Amin Sepehr
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - Niloofar Hejazifar
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Maliheh Talebi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahdi Rohani
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran.
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Zhang S, Cao Y, Wang Z, Liu H, Teng Y, Li G, Liu J, Xia X. Fermented Sargassum fusiforme Mitigates Ulcerative Colitis in Mice by Regulating the Intestinal Barrier, Oxidative Stress, and the NF-κB Pathway. Foods 2023; 12:foods12101928. [PMID: 37238746 DOI: 10.3390/foods12101928] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/05/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
In recent years, Sargassum fusiforme has gained increasing attention for its ability to improve human health and reduce the risk of disease. Nevertheless, there have been few reports on the beneficial functions of fermented Sargassum fusiforme. In this study, the role of fermented Sargassum fusiforme in the mitigation of ulcerative colitis was investigated. Both fermented and unfermented Sargassum fusiforme demonstrated significant improvement in weight loss, diarrhea, bloody stools, and colon shortening in mice with acute colitis. Fermented Sargassum fusiforme further protected against goblet cell loss, decreased intestinal epithelium permeability, and enhanced the expression of tight junction proteins. Fermented Sargassum fusiforme reduced oxidative stress, which was demonstrated by a decrease in nitric oxide (NO), myeloperoxidase (MPO), and malondialdehyde (MDA) concentrations in the colon of mice and an increase in total superoxide dismutase (T-SOD) activity in the colon. Meanwhile, catalase (CAT) concentrations in both the colon and serum of mice were significantly increased. Fermented Sargassum fusiforme also attenuated the inflammatory response, which was evidenced by the decreased level of pro-inflammatory cytokines in the colon. Moreover, fermented Sargassum fusiforme inhibited the nuclear factor-κB (NF-κB) signaling pathway and increased the production of short-chain fatty acids in the intestine. These findings indicate that fermented Sargassum fusiforme may have the potential to be developed as an alternative strategy for alleviating colitis.
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Affiliation(s)
- Siteng Zhang
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Yu Cao
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Zixuan Wang
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Huanhuan Liu
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Yue Teng
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Guopeng Li
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Jiaxiu Liu
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Xiaodong Xia
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
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Levine AE, Mark D, Smith L, Zheng HB, Suskind DL. Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases. Pharmaceutics 2023; 15:969. [PMID: 36986830 PMCID: PMC10059893 DOI: 10.3390/pharmaceutics15030969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD.
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Affiliation(s)
- Anne E. Levine
- Division of Gastroenterology, Seattle Children’s Hospital, Seattle, WA 98105, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Dominique Mark
- Department of Pharmacy, Seattle Children’s Hospital, Seattle, WA 98105, USA
| | - Laila Smith
- Division of Gastroenterology, Seattle Children’s Hospital, Seattle, WA 98105, USA
| | - Hengqi B. Zheng
- Division of Gastroenterology, Seattle Children’s Hospital, Seattle, WA 98105, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - David L. Suskind
- Division of Gastroenterology, Seattle Children’s Hospital, Seattle, WA 98105, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
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Rosh JR. Methotrexate. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:401-406. [DOI: 10.1007/978-3-031-14744-9_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Methotrexate for Primary Maintenance Therapy in Mild-to-Moderate Crohn Disease in Children. J Pediatr Gastroenterol Nutr 2022; 75:320-324. [PMID: 35758420 DOI: 10.1097/mpg.0000000000003543] [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] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Despite limited data, methotrexate (MTX) is often used as primary maintenance therapy in pediatric Crohn disease (CD). We sought to assess the effectiveness of MTX as "initial" primary maintenance therapy in newly diagnosed mild/moderate pediatric CD and ascertain baseline predictive factors. METHODS Single-center 10-year retrospective review of newly diagnosed CD patients treated with MTX as primary maintenance therapy. We compared baseline characteristics of those patients with sustained response/clinical remission to those patients who escalated to anti-TNF therapy within 1 year. Pediatric Crohn Disease Activity Index (PCDAI) ≤ 10 defined remission. RESULTS We identified 65 patients (mean age, 11.8 years; 72 % male; mean ± SD PCDAI, 17.8 ± 10.5) who started MTX ≤4 months of diagnosis as their primary maintenance therapy. Initial therapy prior to MTX was corticosteroids (CS) (54/65), defined diet (4/65), and combination CS/diet (6/65). Oral dosing was used in 55%; mean dose was 11.4 mg/m 2 orally and 12.5 mg/m 2 subcutaneously. At 1 year, 36 of 65 (55%) were on MTX monotherapy, and of those, 32 of 36 were in clinical remission; 81% were in steroid-free remission for the year following induction. For the 36 patients on MTX at 1 year, 14 (39%) had gross mucosal healing (22% of the original cohort). Ten additional patients had mucosal improvement (37% of total healed/improved). Fifteen patients (23%) were early failures, transitioning to anti-TNF ≤4 months. Baseline PCDAI, hemoglobin, ESR, albumin, and route of administration were not predictive of outcome. MTX was well tolerated in our cohort, with only 1 patient stopping due to elevated aminotransferases. No patient required CD surgery in the 1-year follow-up. CONCLUSIONS MTX may have a primary maintenance role in mild/moderate CD.
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Pediatric Management of Crohn's Disease. Gastroenterol Clin North Am 2022; 51:401-424. [PMID: 35595422 DOI: 10.1016/j.gtc.2021.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Pediatric Crohn's disease is often more severe, requires higher levels of immunosuppression, and is associated with greater morbidity compared with adult Crohn's disease. Unique considerations in pediatric Crohn's disease include growth impairment, pubertal delay, bone disease, longevity of disease burden, and psychosocial impact. Treatment options are limited, requiring off-label use of therapy in this challenging patient population. Understanding the medications available, the existing evidence supporting their use, and side effects is important. There is tremendous potential for growth and improvement in this field and it is essential that all gastroenterologists have an understanding of this complex and unique patient population.
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Nejati S, Wang J, Heredia-Rivera U, Sedaghat S, Woodhouse I, Johnson JS, Verma M, Rahimi R. Small intestinal sampling capsule for inflammatory bowel disease type detection and management. LAB ON A CHIP 2021; 22:57-70. [PMID: 34826326 DOI: 10.1039/d1lc00451d] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Although serum and fecal biomarkers (e.g., lactoferrin, and calprotectin) have been used in management and distinction between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), none are proven to be a differential diagnostic tool between Crohn's disease (CD) and ulcerative colitis (UC). The main challenge with laboratory-based biomarkers in the stool test is the inability to indicate the location of the disease/inflammation in the gastrointestinal (GI) tract due to the homogenous nature of the collected fecal sample. For the first time, we have designed and developed a battery-free smart capsule that will allow targeted sampling of inflammatory biomarkers inside the gut lumen of the small intestine. The capsule is designed to provide a simple and non-invasive complementary tool to fecal biomarker analysis to differentiate the type of IBD by pinpointing the site of inflammatory biomarkers secretion (e.g., small or large bowel) throughout the GI tract. The capsule takes advantage of the rapid change from an acidic environment in the stomach to higher pH levels in the small intestine to dissolve a pH-sensitive polymeric coating as a means to activate the sampling process of the capsule within the small intestine. A swelling polyacrylamide hydrogel is placed inside the capsule as a milieu to collect the sampled GI fluid while also providing the required mechanical actuation to close the capsule once the sampling is completed. The hydrogel component along with the collected GI fluid can be easily obtained from the capsule through the screw-cap design for further extraction and analysis. As a proof of concept, the capsule's performance in sampling and extraction of bovine serum albumin (BSA) and calprotectin - a key biomarker of inflammation - was assessed within the physiologically relevant ranges. The ratio of extracted biomarkers relative to that in the initial sampling environment remained constant (∼3%) and independent of the sampling matrix in both in vitro and ex vivo studies. It is believed that the demonstrated technology will provide immediate impact in more effective IBD type differential diagnostic and treatment strategies by providing a non-invasive assessment of inflammation biomarkers profile throughout the digestive tract.
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Affiliation(s)
- Sina Nejati
- School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
| | - Jiangshan Wang
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Ulisses Heredia-Rivera
- School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
| | - Sotoudeh Sedaghat
- School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
| | - Ian Woodhouse
- School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
| | - Jay S Johnson
- USDA-ARS Livestock Behavior Research Unit, West Lafayette, IN 47907, USA
| | - Mohit Verma
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Rahim Rahimi
- School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN, 47907, USA
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Poda O. Болезнь Крона у детей: актуальные аспекты диагностики и лечения согласно современным международным рекомендациям. CHILD`S HEALTH 2021; 16:75-83. [DOI: 10.22141/2224-0551.16.1.2021.226461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
В статье обобщены знания об эпидемиологических данных, клинических особенностях, современных принципах диагностики и лечения болезни Крона у детей на основе анализа литературных источников с использованием бумажных носителей и электронных баз данных PubMed, CyberLeninka, Web of Science, MedLine, The Cochrane Library. Обзор литературных источников по изучению данной патологии показывает, что на современном этапе диагностика воспалительных заболеваний кишечника, особенно у детей раннего возраста, все еще остается сложным вопросом. Обозначена проблема трудностей диагностического поиска вследствие не всегда типичного течения заболевания в детском возрасте. Приведены данные об особенностях клинического течения заболевания в зависимости от локализации патологического процесса. Автором также отдельно акцентирована важность ранней диагностики болезни Крона с целью проведения своевременного протокольного лечения и необходимость распознавания данной патологии уже на уровне первичной медицинской помощи. В статье также приведены данные Европейского общества детской гастроэнтерологии, гепатологии и питания и Европейской организации по изучению болезни Крона и колита относительно необходимого объема методов диагностики болезни Крона у детей согласно современным международным рекомендациям. Обзор освещает современные принципы лечения болезни Крона у детей, описаны основные фармакологические группы лекарственных средств, которые имеют доказательную базу эффективности в педиатрической практике. Особое внимание уделено роли полного энтерального питания как наиболее безопасного и достаточно эффективного направления стартовой терапии данной патологии у детей. В заключение автор освещает проблему дифференциальной диагностики воспалительных заболеваний кишечника в педиатрической практике.
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van Rheenen PF, Aloi M, Assa A, Bronsky J, Escher JC, Fagerberg UL, Gasparetto M, Gerasimidis K, Griffiths A, Henderson P, Koletzko S, Kolho KL, Levine A, van Limbergen J, Martin de Carpi FJ, Navas-López VM, Oliva S, de Ridder L, Russell RK, Shouval D, Spinelli A, Turner D, Wilson D, Wine E, Ruemmele FM. The Medical Management of Paediatric Crohn's Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis 2020; 15:jjaa161. [PMID: 33026087 DOI: 10.1093/ecco-jcc/jjaa161] [Citation(s) in RCA: 308] [Impact Index Per Article: 61.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]. METHODS We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained. RESULTS We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone. CONCLUSIONS We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.
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Affiliation(s)
- Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | - Amit Assa
- Department of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petach Tikvah, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Jiri Bronsky
- Paediatric Gastroenterology Unit, Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Johanna C Escher
- Department of Paediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ulrika L Fagerberg
- Department of Pediatrics/Centre for Clinical Research, Västmanland Hospital, Västeras and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Marco Gasparetto
- Department of Paediatric Gastroenterology, Barts Health Trust, The Royal London Children's Hospital, London, UK
| | | | - Anne Griffiths
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Paul Henderson
- Child Life and Health, University Of Edinburgh, Edinburgh, UK
| | - Sibylle Koletzko
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Kaija-Leena Kolho
- Department of Paediatrics, Children´s Hospital, University of Helsinki and Tampere University, Tampere, Finland
| | - Arie Levine
- Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Tel Aviv University, Israel
| | - Johan van Limbergen
- Division of Pediatric Gastroenterology and Nutrition, Amsterdam UMC - location AMC, Amsterdam, The Netherlands
| | | | - Víctor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Salvatore Oliva
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Richard K Russell
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
| | - Dror Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Antonino Spinelli
- Department of Colon and Rectal Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano Milano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Dan Turner
- Paediatric Gastroenterology, Shaare Zedek Medical Centre, the Hebrew University of Jerusalem, Israel
| | - David Wilson
- Child Life and Health, University Of Edinburgh, Edinburgh, UK
| | - Eytan Wine
- Division of Pediatric Gastroenterology, Edmonton Pediatric IBD Clinic (EPIC), Departments of Pediatrics & Physiology, University of Alberta, Edmonton, Canada
| | - Frank M Ruemmele
- Assistance Publique- Hôpitaux de Paris, Hôpital Necker Enfants Malades, Pediatric Gastroenterology, Paris, France
- Faculté de Médecine, Université Sorbonne Paris Cité, Paris Descartes, Paris, France
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Vuerich M, Mukherjee S, Robson SC, Longhi MS. Control of Gut Inflammation by Modulation of Purinergic Signaling. Front Immunol 2020; 11:1882. [PMID: 33072065 PMCID: PMC7544737 DOI: 10.3389/fimmu.2020.01882] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/13/2020] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.
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Affiliation(s)
- Marta Vuerich
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Samiran Mukherjee
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Simon C Robson
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.,Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Maria Serena Longhi
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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Harris RE, Aloi M, de Ridder L, Croft NM, Koletzko S, Levine A, Turner D, Veereman G, Neyt M, Bigot L, Ruemmele FM, Russell RK. Protocol for a multinational risk-stratified randomised controlled trial in paediatric Crohn's disease: methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or high risk for aggressive disease course. BMJ Open 2020; 10:e034892. [PMID: 32611737 PMCID: PMC7332179 DOI: 10.1136/bmjopen-2019-034892] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups. AIMS To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation. METHODS AND ANALYSIS REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk). ETHICS AND DISSEMINATION ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access. TRIAL REGISTRATION NUMBER NCT02852694; Pre-results.
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Affiliation(s)
- Rachel E Harris
- Department of Paediatric Gastroenterology, Royal Hospital for Children Glasgow, Glasgow, UK
| | - Marina Aloi
- Paediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Roma, Lazio, Italy
| | - Lissy de Ridder
- Paediatrics, Erasmus MC/Sophia Childrens Hospital, Rotterdam, The Netherlands
| | - Nicholas M Croft
- Department of Paediatric Gastroenterology, Barts and The London School of Medicine and Dentistry, London, UK
| | - Sibylle Koletzko
- Pediatric Gastroenterology and Hepatology, Dr. V. Hauner Children's Hospital, Munich, Germany
- Department of Pediatrics, Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Arie Levine
- Edith Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Dan Turner
- Department of Paediatric Gastroenterology, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gigi Veereman
- Pediatric GI, UZBrussels-VUB, Brussels, Belgium
- Free University Brussels, University Hospital, Brussels, Belgium
| | - Mattias Neyt
- ME-TA Medical Evaluation and Technology Assessment, Merendree, Belgium
| | - Laetitia Bigot
- PIBD-Net, Hôpital universitaire Necker-Enfants malades, Paris, Île-de-France, France
| | - Frank M Ruemmele
- Service de Gastroentérologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Paris, Île-de-France, France
- Department of Paediatric Gastroenterology, Université Paris Descartes, Paris, Île-de-France, France
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Children Glasgow, Glasgow, UK
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Khan I, Ullah N, Zha L, Bai Y, Khan A, Zhao T, Che T, Zhang C. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens 2019; 8:pathogens8030126. [PMID: 31412603 PMCID: PMC6789542 DOI: 10.3390/pathogens8030126] [Citation(s) in RCA: 467] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/03/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD.
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Affiliation(s)
- Israr Khan
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Naeem Ullah
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Lajia Zha
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Yanrui Bai
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Ashiq Khan
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Probiotics and Biological Feed Research Center, Lanzhou University, Lanzhou 730000, China
| | - Tang Zhao
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Tuanjie Che
- Gansu Key Laboratory of Functional Genomics and Molecular Diagnosis, Lanzhou 730000, China
| | - Chunjiang Zhang
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China.
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China.
- Gansu Key Laboratory of Functional Genomics and Molecular Diagnosis, Lanzhou 730000, China.
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Irvine AD, Jones AP, Beattie P, Baron S, Browne F, Ashoor F, O'Neill L, Rosala-Hallas A, Sach T, Spowart C, Taams L, Walker C, Wan M, Webb N, Williamson P, Flohr C. A randomized controlled trial protocol assessing the effectiveness, safety and cost-effectiveness of methotrexate vs. ciclosporin in the treatment of severe atopic eczema in children: the TREatment of severe Atopic eczema Trial (TREAT). Br J Dermatol 2018; 179:1297-1306. [PMID: 29727479 DOI: 10.1111/bjd.16717] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2018] [Indexed: 11/27/2022]
Abstract
BACKGROUND Oral systemic immunomodulatory medication is regularly used off-licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost-effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children. OBJECTIVES To assess whether there is a difference in the speed of onset, effectiveness, side-effect profile and reduction in flares post-treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost-effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune-metabolic effects of CyA and MTX. METHODS Multicentre, parallel group, assessor-blind, pragmatic RCT of 36 weeks' duration with a 24-week follow-up period. In total, 102 children aged 2-16 years with moderate-to-severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg-1 per week) or CyA (4 mg kg-1 per day). RESULTS The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare following treatment cessation. CONCLUSIONS This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice.
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Affiliation(s)
- A D Irvine
- Clinical Medicine, Trinity College Dublin, Dublin, Ireland.,Paediatric Dermatology, Our Lady's Children Hospital Crumlin, Dublin, Ireland.,National Children's Research Centre, Crumlin, Dublin, Ireland
| | - A P Jones
- Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, U.K
| | - P Beattie
- Royal Hospital for Children NHS Trust, Glasgow, U.K
| | - S Baron
- Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K
| | - F Browne
- Paediatric Dermatology, Our Lady's Children Hospital Crumlin, Dublin, Ireland
| | - F Ashoor
- Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, U.K
| | - L O'Neill
- Biochemistry, Trinity College Dublin, Dublin, Ireland
| | - A Rosala-Hallas
- Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, U.K
| | - T Sach
- Health Economics Group, Norwich Medical School, University of East Anglia, Norwich, U.K
| | - C Spowart
- Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, U.K
| | - L Taams
- Centre for Molecular and Cellular Biology of Inflammation, King's College London, London, U.K
| | - C Walker
- Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K
| | - M Wan
- Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K
| | - N Webb
- Renal Research Laboratories, Manchester Royal Infirmary, Manchester, U.K
| | - P Williamson
- Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, U.K
| | - C Flohr
- Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K
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- Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, U.K
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Colman RJ, Lawton RC, Dubinsky MC, Rubin DT. Methotrexate for the Treatment of Pediatric Crohn's Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 2018; 24:2135-2141. [PMID: 29688409 PMCID: PMC6994018 DOI: 10.1093/ibd/izy078] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate (MTX) is an immunomodulator used for the treatment of pediatric inflammatory bowel disease (IBD). There are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis assesses the efficacy of MTX therapy among the existing pediatric literature. METHODS A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Synonyms for 'pediatric', 'methotrexate' and 'IBD' were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18 yrs old, as mono- or combination therapy. Case studies with <10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates. A random-effects meta-analysis with forest plots was performed using R. RESULTS Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 202 studies. No interventional studies were identified. The pooled achieved CR rate for pediatric CD patients on monotherapy within 3-6 months was 57.7% (95% CI 48.2-66.6%), (P =0.22; I2 = 29.8%). The CR was 37.1% (95% CI 29.5-45.5%), (P = 0.20; I2 = 37.4%) for maintenance therapy at 12 months. Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposure. CONCLUSIONS This meta-analysis demonstrated that, over 50% of pediatric Crohn's disease patients induced with methotrexate achieved clinical remission, while 12-month remission rate was only 37%. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups. 10.1093/ibd/izy078_video1izy078.video15774883936001.
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Affiliation(s)
- Ruben J Colman
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois,Pediatrics, SBH Health System, Bronx, New York
| | | | | | - David T Rubin
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois,Address correspondence to: David T. Rubin, MD, 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637 ()
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Absorption of Codonopsis pilosula Saponins by Coexisting Polysaccharides Alleviates Gut Microbial Dysbiosis with Dextran Sulfate Sodium-Induced Colitis in Model Mice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1781036. [PMID: 30211217 PMCID: PMC6120299 DOI: 10.1155/2018/1781036] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/22/2018] [Accepted: 07/05/2018] [Indexed: 12/16/2022]
Abstract
Objectives Inflammatory Bowel Disease (IBD) is an autoimmune disease, and the gut microbiota has become a new therapeutic target. Herbal medicine (HM) has shown good efficacy in the clinical treatment of IBD; however, the synergistic actions of the dominant chemicals in HM decoctions are unclear. Methods In this study, we explored whether the complicated interconnections between HM and the gut microbiota could allow crosstalk between HM ingredients. Saponins and polysaccharides, i.e., the dominant chemicals in the Codonopsis pilosula Nannf (CPN) decoction, were investigated in a dextran sulfate sodium- (DSS-) induced mouse model. Bacterial 16S rRNA sequencing analyzed the change of gut microbiota structure and diversity. Gas chromatography (GC) determined the content of short-chain fatty acids (SCFAs) in feces. ELISA detected the expression of proinflammatory and anti-inflammatory cytokines associated with TH17/Treg balance. UPLC-QTOF-MS technology combined with PKsolver software analyzed the absorption of the highest exposure for monomeric compounds of CPN saponins in serum. The results indicated that CPN polysaccharides showed prebiotic-like effects in mice with DSS-induced colitis by simultaneously stimulating the growth of three important probiotics, i.e., Bifidobacterium spp., Lactobacillus spp., and Akkermansia spp., and inhibiting the growth of pathogenic bacteria, including Desulfovibrio spp., Alistipes spp., and Helicobacter spp. Moreover, CPN polysaccharides improved intestinal metabolism, enhanced the production of short-chain fatty acids, upregulated the expression of anti-inflammatory cytokines and downregulated the secretion of proinflammatory cytokines correlated with Th17/Treg balance, promoted the absorption of certain CPN saponins in the serum, and stimulated recovery of the holistic gut microbiota. Conclusion CPN polysaccharides have the good prebiotic properties and shown good application prospects in the prevention and treatment of acute colitis. These findings provide insights into the specific bacteria responsible for active, inactive biotransformation of HM ingredients and those that are altered by HM administration.
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Djurić Z, Šaranac L, Budić I, Pavlović V, Djordjević J. Therapeutic role of methotrexate in pediatric Crohn's disease. Bosn J Basic Med Sci 2018; 18:211-216. [PMID: 29338679 DOI: 10.17305/bjbms.2018.2792] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 01/07/2018] [Accepted: 01/08/2018] [Indexed: 12/30/2022] Open
Abstract
The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in CD include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate (MTX). Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines only or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of MTX in children suffering from CD. This review summarizes the literature on the therapeutic role of MTX in children with CD. MTX is often administered as a second-line immunomodulator, and 1-year clinical remission was reported in 25-69% of children with CD after excluding for the use of thiopurines. Initial data on MTX effectiveness in mucosal healing, and as a first-line immunomodulator in pediatric patients with CD, are promising. A definite conclusion, however, may only be made on the basis of additional research with a larger number of subjects.
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Affiliation(s)
- Zlatko Djurić
- Division of Gastroenterology, Children's Hospital, Faculty of Medicine, University of Niš, Niš, Serbia.
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Management of unclassified inflammatory bowel disease in children requires an individualized approach. DRUGS & THERAPY PERSPECTIVES 2017. [DOI: 10.1007/s40267-017-0451-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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D'Arcangelo G, Aloi M. Inflammatory Bowel Disease-Unclassified in Children: Diagnosis and Pharmacological Management. Paediatr Drugs 2017; 19:113-120. [PMID: 28150131 DOI: 10.1007/s40272-017-0213-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Inflammatory bowel diseases are chronic disorders of the gastrointestinal tract that include Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease-unclassified (IBDU). The latter defines a subgroup of patients with clinical and endoscopic evidence of chronic colitis, without specific features of either CD or UC. These patients will possibly be re-classified as having UC or CD during the follow-up, although a significant percentage of them will keep the diagnosis of IBDU. IBDU is the rarest subtype of IBD, both in children and in adults, although it is twice as common among the pediatric population, especially in the younger ages. The diagnosis can only be made after a comprehensive diagnostic work-up, combining clinical history, physical and laboratory examination, upper and lower gastrointestinal endoscopy, with histology and imaging of the small bowel. The therapeutic strategy is borrowed from that of UC and CD, although recent data suggest that IBDU has a lower therapeutic burden with a generally mild disease course and a good response to mesalamine. Since there are only few published data on pediatric IBDU, and no guidelines on its management are available, this review aims at summarizing the most recent evidence for the diagnostic work-up with a specific focus on medical and surgical options in the treatment of IBDU.
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Affiliation(s)
- Giulia D'Arcangelo
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Marina Aloi
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
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Prevalence and Risk Factors for Symptoms of Methotrexate Intolerance in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23:298-303. [PMID: 28107279 DOI: 10.1097/mib.0000000000001014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate (MTX) intolerance is defined as gastrointestinal and behavioral symptoms occurring before or after MTX administration that may lead to treatment discontinuation. The aim of this study was to determine prevalence of MTX intolerance in pediatric inflammatory bowel disease (IBD) using the Methotrexate Intolerance Severity Score developed in rheumatology and to identify risk factors for MTX intolerance. METHODS Patients with pediatric IBD followed in the IBD clinic of Sainte Justine Hospital who had received MTX for IBD between 2004 and 2016 and were still actively on MTX were invited to fill out the Methotrexate Intolerance Severity Score questionnaire. A cutoff score of ≥6 points was used to define MTX intolerance, with at least one point for anticipatory, associative or behavioral items. RESULTS Among 102 pediatric patients with IBD, 32 (31%) patients reported symptoms of MTX intolerance. Using a multivariable logistic regression model, factors that were associated with having symptoms of MTX intolerance were female sex (odds ratio 4.31 [95% confidence interval, 1.37-13.60], P = 0.01), receiving a dose of MTX higher than 20 mg/wk at the time of the questionnaire (odds ratio 4.06 [95% confidence interval, 1.30-12.70], P = 0.02), and having active disease according to Physician's Global Assessment (odds ratio 3.44 [95% confidence interval, 1.15-10.26], P = 0.03). Prophylactic prescription of antiemetics and folic acid did not prevent symptoms of MTX intolerance. CONCLUSIONS Symptoms of MTX intolerance are frequent in pediatric IBD. The Methotrexate Intolerance Severity Score questionnaire could help better recognition of these symptoms. Identification of risk factors could have important implications for the success of treatment.
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Rosh JR. Methotrexate. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2017:383-388. [DOI: 10.1007/978-3-319-49215-5_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Methotrexate is commonly used in rheumatoid arthritis but randomised controlled trials demonstrated its efficacy also in Crohn's disease. Methotrexate, although marginally used in clinical practice, is considered an appropriate immunomodulator particularly in patients refractory or intolerant to thiopurines. Areas covered: A literature search using 'methotrexate', 'Crohn's disease' and 'Inflammatory Bowel Disease' as key words, identified randomised controlled trials, meta-analyses and observational studies. The aim of this review is to summarise and critically discuss the available evidence concerning the efficacy and safety of methotrexate in the treatment of Crohn's disease. Expert commentary: Methotrexate is effective in inducing and maintaining remission in steroid-dependent CD at a dose of 25 mg/week and 15 mg/week, respectively. Data from observational studies suggest that methotrexate may be as efficacious as thiopurines with a similar safety profile. In specific clinical settings, (patients with a history of malignancy or young Epstein-Barr Virus-seronegative patients), methotrexate compete favourably with thiopurines.
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Affiliation(s)
- Monica Cesarini
- a Department of Internal Medicine , University of Rome La Sapienza , Rome , Italy
| | - Stefano Festa
- b IBD Unit , San Filippo Neri Hospital , Rome , Italy
| | - Claudio Papi
- b IBD Unit , San Filippo Neri Hospital , Rome , Italy
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Aloi M, Birimberg-Schwartz L, Buderus S, Hojsak I, Fell JM, Bronsky J, Veereman G, Koletzko S, Shaoul R, Miele E, Turner D, Russell RK. Treatment Options and Outcomes of Pediatric IBDU Compared with Other IBD Subtypes: A Retrospective Multicenter Study from the IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2016; 22:1378-83. [PMID: 27135479 DOI: 10.1097/mib.0000000000000767] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammatory bowel disease unclassified (IBDU) is the rarest IBD subtype with treatment based on extrapolation from ulcerative colitis (UC) and Crohn's disease (CD) studies. We compared IBDU treatment choices with other colonic IBDs and explored long-term outcomes. METHODS This was a multicenter retrospective longitudinal study of 23 centers of pediatric IBD with isolated colitis, including a mild ileitis consistent with backwash. RESULTS Of note, 797 children (median age: 11.6 years, range: 2-18.4) were included: 250 with CD, 287 with UC, and 260 with IBDU (median follow-up: 2.8 [interquartile range: 1.6-4.2] years). IBDU differed from UC with lower corticosteroid (154 [59%] versus 204 [71%]; P = 0.004) and higher exclusive enteral nutrition use (26 [10%] versus 2 [0.6%]; P < 0.0001). Compared to patients with CD, patients with IBDU received less exclusive enteral nutrition and immunomodulators (26 [10%] versus 93 [37%]; P < 0.0001 and 67 [26%] versus 129 [52%]; P < 0.0001, respectively) but more aminosalicylates (228 [88%] versus 159 [64%]; P < 0.0001). Biological treatment was significantly higher in CD (82 [34%]) than in IBDU and UC (24 [12%] and 47 [17%], respectively; P < 0.0001). At last follow-up, 135 (69%) patients with IBDU had remission/mild disease activity compared with 100 (46%; P < 0.0001) patients with CD and 174 (64%; P = 0.3) patients with UC. Four (2%) of 194 patients with IBDU underwent surgery compared with 22 (8%) of 270 patients with UC (P = 0.009) and 20 (8%) of 238 patients with CD (P = 0.008). CONCLUSIONS Children with IBDU have a lower medication burden and lower surgery rates than other IBD subtypes. The disease course at follow-up is generally mild, supporting an initial trial with 5-ASA before using more aggressive therapies.
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Affiliation(s)
- Marina Aloi
- *Sapienza University of Rome, Rome, Italy; †Shaare Zedek Medical Center, Jerusalem, Israel; ‡Department of Pediatrics, St. Marien-Hospital, Bonn, Germany; §Children's Hospital Zagreb, Zagreb, Croatia; ‖Chelsea and Westminster Hospital, London, United Kingdom; ¶Department of Paediatrics, Charles University and University Hospital Motol, Prague, Czech Republic; **Free University Brussels, Brussels, Belgium; ††Ludwig Maximilians University, Munich, Germany; ‡‡Rambam Medical Center, Haifa, Israel; §§University of Naples "Federico," Naples, Italy; ‖‖The Hebrew University, Jerusalem, Israel; and ¶¶Royal Hospital for Children, Glasgow, United Kingdom
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Hojsak I, Mišak Z, Jadrešin O, Močić Pavić A, Kolaček S. Methotrexate is an efficient therapeutic alternative in children with thiopurine-resistant Crohn's disease. Scand J Gastroenterol 2016; 50:1208-13. [PMID: 25877164 DOI: 10.3109/00365521.2015.1031166] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE This study aimed to investigate the role of methotrexate (MTX) in the maintenance of clinical remission and mucosal healing in children with Crohn's disease (CD), in whom azathioprine (AZA) treatment failed. MATERIALS AND METHODS This was a retrospective, longitudinal cohort study which included all children who were diagnosed with CD during a period of 10 years and who received MTX for ≥12 months after failed AZA treatment. Remission was assessed clinically, defined by Pediatric Crohn's Disease Activity Index as a score of ≤10 and no need for the reintroduction of the remission induction therapy. In the subset of patients with sustained clinical remission, the rate of mucosal healing was endoscopically assessed. Endoscopic lesions were assessed by Simple Endoscopic Score for CD. Each patient served as his or her own historical control. RESULTS Of the 32 included patients, 22 (68.7%) remained in the stable clinical remission after a period of 12 months and 14 (43.8%) did not experience relapse during the whole follow up (median duration 2.9 years; range 1-4.8 years). From all patients who were in clinical remission during the entire follow up (n = 14), endoscopy was performed in eight (57%) patients and showed complete mucosal healing macroscopically (Simple Endoscopic Score for CD score of 0) and microscopically in seven out of eight (87.5%) patients. CONCLUSION MTX was found to be an efficient therapeutic alternative in the thiopurine-resistant patients, enabling the complete mucosal healing.
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Affiliation(s)
- Iva Hojsak
- Referral Center for Pediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, University of Zagreb Medical School , Zagreb , Croatia
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Kammermeier J, Morris MA, Garrick V, Furman M, Rodrigues A, Russell RK. Management of Crohn's disease. Arch Dis Child 2016; 101:475-80. [PMID: 26553907 PMCID: PMC4853609 DOI: 10.1136/archdischild-2014-307217] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/09/2015] [Accepted: 10/12/2015] [Indexed: 02/07/2023]
Abstract
Crohn's disease (CD) is rapidly increasing in children so an up to date knowledge of diagnosis, investigation and management is essential. Exclusive enteral nutrition is the first line treatment for active disease. The vast majority of children will need immunosuppressant treatment and around 20% will need treatment with biologics. Recent guidelines have helped make best use of available therapies.
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Affiliation(s)
| | - Mary-Anne Morris
- Department of Paediatrics, Norfolk and Norwich University Hospital, Norwich, UK
| | - Vikki Garrick
- Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, UK
| | - Mark Furman
- Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK
| | - Astor Rodrigues
- Department of Paediatric Gastroenterology, John Radcliffe Hospital, Oxford, UK
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, UK
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Scherkenbach LA, Stumpf JL. Methotrexate for the Management of Crohn's Disease in Children. Ann Pharmacother 2015; 50:60-9. [PMID: 26511908 DOI: 10.1177/1060028015613527] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE To review the literature evaluating methotrexate as a treatment option for Crohn's disease (CD) in pediatric patients. DATA SOURCES A search of PubMed electronic database (1966 to August 2015) and secondary resources was performed using the terms methotrexate, Crohn's, and inflammatory bowel disease. Other relevant articles cited within identified articles were also utilized. STUDY SELECTION AND DATA EXTRACTION Data sources were limited to English-language studies that included children less than 18 years of age. In total, 10 clinical studies met the criteria. DATA SYNTHESIS Awareness of the risk of hepatosplenic T-cell lymphoma associated with anti-tumor necrosis factor and thiopurine therapies has renewed interest in methotrexate to treat CD in children. According to data from 10 predominantly retrospective studies, children treated with oral or subcutaneous methotrexate once weekly had remission rates of 25% to 53% at 1 year. Adverse effects most often included nausea and vomiting, elevated liver function tests, headache, and hematological toxicity. The evidence to support methotrexate is limited by inconsistent study design and poorly described dosage regimens. It has been most frequently evaluated in patients with prior thiopurine exposure and has not been thoroughly evaluated as first-line therapy. CONCLUSIONS Based on results of retrospective studies, methotrexate is useful in the treatment of pediatric CD in those who fail thiopurine therapy. Remission rates with methotrexate are similar to those for thiopurine therapy, although no studies directly compare these agents. Although preliminary results are promising, prospective studies are needed to assess the use of methotrexate as initial first-line therapy in the pediatric CD population.
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Affiliation(s)
- Lisa A Scherkenbach
- University of Michigan Health System and College of Pharmacy, Ann Arbor, MI, USA
| | - Janice L Stumpf
- University of Michigan Health System and College of Pharmacy, Ann Arbor, MI, USA
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Wang Y, MacDonald JK, Vandermeer B, Griffiths AM, El‐Matary W. Methotrexate for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2015; 2015:CD007560. [PMID: 26263042 PMCID: PMC6486092 DOI: 10.1002/14651858.cd007560.pub3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis. OBJECTIVES The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH METHODS We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia AUTHORS' CONCLUSIONS The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.
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Affiliation(s)
- Yongjun Wang
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - John K MacDonald
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - Ben Vandermeer
- University of AlbertaDepartment of Pediatrics4‐496B Edmonton Clinic Health Academy (ECHA)11405 ‐ 87 AvenueEdmontonABCanadaT6G 1C9
| | - Anne Marie Griffiths
- The Hospital for Sick ChildrenDivision of Gastroenterology, Hepatology & Nutrition555 University Ave.TorontoONCanadaM5G 1X8
| | - Wael El‐Matary
- Children's Hospital, Health Sciences CentreSection of Pediatric GastroenterologyAE‐408840 Sherbrook St.WinnipegMBCanadaR3A 1S1
- University of ManitobaDepartment of Pediatrics, Faculty of MedicineWinnipegMBCanada
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Lahad A, Weiss B. Current therapy of pediatric Crohn’s disease. World J Gastrointest Pathophysiol 2015; 6:33-42. [PMID: 25977836 PMCID: PMC4419092 DOI: 10.4291/wjgp.v6.i2.33] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate, antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor (TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy - induction and maintenance of remission while improving the patient’s growth and overall well-being.
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Haisma SM, Lijftogt T, Kindermann A, Damen G, de Ridder L, Escher JC, Mearin ML, de Meij T, Hendriks D, George E, Hummel T, Norbruis O, van Rheenen P. Methotrexate for maintaining remission in paediatric Crohn's patients with prior failure or intolerance to thiopurines: a multicenter cohort study. J Crohns Colitis 2015; 9:305-11. [PMID: 25656249 DOI: 10.1093/ecco-jcc/jjv031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Methotrexate [MTX] is an immunomodulating drug that can be used to maintain remission in patients with Crohn's disease [CD], but data on efficacy and tolerability in children and teenagers are scarce. We evaluated the long-term efficacy and tolerability of MTX monotherapy after thiopurine therapy in paediatric CD patients. METHODS A multicenter cohort of paediatric MTX users who stopped thiopurines due to ineffectiveness or intolerance between 2002 and 2012 were included and followed for at least 12 months. Relapse-free use was defined as steroid and biologics-free clinical remission after the introduction of MTX, and included intentional discontinuation of successful therapy before the end of the observation period. RESULTS A total of 113 patients with CD in remission were followed while on MTX monotherapy, of whom 75 [66%] had failed on thiopurines and 38 [34%] had stopped thiopurines due to side effects. Median age at the introduction of MTX was 14 years [range 7 to 17], and 93% used the subcutaneous route. Kaplan-Meier analysis showed that 52% of the study cohort were still in steroid- and biologics-free remission after 12 months of MTX monotherapy, with a difference that did not reach significance between thiopurine-intolerant and thiopurine-failing patients [p = 0.21, log-rank test]. CONCLUSIONS The findings of this cohort study suggest that MTX is an effective immunomodulator to maintain remission after stopping thiopurines. MTX maintenance should be considered before stepping up to anti-tumor necrosis factor alpha therapy. MTX is probably somewhat more effective in patients who stopped thiopurines due to side effects than in those who failed on thiopurines.
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Affiliation(s)
- Sjoukje-Marije Haisma
- University of Groningen, University Medical Center Groningen, Department of Pediatric Gastroenterology, Groningen, The Netherlands
| | - Thijs Lijftogt
- University of Groningen, University Medical Center Groningen, Department of Pediatric Gastroenterology, Groningen, The Netherlands
| | - Angelika Kindermann
- Emma's Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands
| | - Gerard Damen
- Department of Pediatrics, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
| | - Lissy de Ridder
- Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Johanna C Escher
- Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - M Luisa Mearin
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Tim de Meij
- VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Daniëlle Hendriks
- Juliana Children's Hospital/Haga Teaching Hospital, The Hague, The Netherlands
| | | | | | - Obbe Norbruis
- Isala, Princess Amalia Department of Pediatrics, Zwolle, The Netherlands
| | - Patrick van Rheenen
- University of Groningen, University Medical Center Groningen, Department of Pediatric Gastroenterology, Groningen, The Netherlands
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Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: State of the art and future perspectives. World J Gastroenterol 2015; 21:21-46. [PMID: 25574078 PMCID: PMC4284336 DOI: 10.3748/wjg.v21.i1.21] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/31/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Distinction between Crohn’s disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
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Abstract
OBJECTIVES Children and adolescents diagnosed as having Crohn disease (CD), a type of inflammatory bowel disease (IBD), have increased vulnerability for anxiety symptoms that may be related to disease-related processes. The aims of this article are 3-fold: to report the proportion of pediatric patients with CD whose self-reported anxiety symptoms are indicative of distress, to describe the constellation of anxiety symptoms, and to examine the relation between anxiety and disease symptoms. METHODS Retrospective medical chart review was performed for 93 youths with CD (ages 9-18 years) who had completed the Screen for Child Anxiety Related Disorders during their gastroenterology visit. Medical records were reviewed for demographic and disease characteristics. the Harvey-Bradshaw Index (HBI) was used as a measure of CD activity. RESULTS Thirty percent of the youths reported experiencing elevated anxiety symptoms (Screen for Child Anxiety Related Disorder score >20), and 50% had scored above the cutoff in 1 or more anxiety domains, with school anxiety, general anxiety, and separation anxiety symptoms reported most frequently. Youth rated with moderate/severe disease activity on the HBI (n = 4) self-reported more anxiety symptoms compared with youth with inactive disease (n = 78, P = 0.03). Greater school anxiety was significantly associated with decreased well-being (P = 0.003), more abdominal pain (P < 0.001), and the number of loose stools (P = 0.01). Having extraintestinal symptoms was significantly associated with higher somatic/panic anxiety (P = 0.01). CONCLUSIONS Implementing a brief anxiety screen in tertiary pediatric settings may be one approach to identify young patients with CD in distress. Health care providers should consider periodic assessment of school anxiety among youth with CD.
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Gomollón F, Rubio S, Charro M, García-López S, Muñoz F, Gisbert JP, Domènech E. [Reccomendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of methotrexate in inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 38:24-30. [PMID: 25454602 DOI: 10.1016/j.gastrohep.2014.10.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 10/09/2014] [Indexed: 12/17/2022]
Abstract
Methotrexate is an immunosuppressant that may be useful in several clinical scenarios in inflammatory bowel disease. In this article, we review the available evidence in Crohn's disease and ulcerative colitis and establish general recommendations for its use in clinical practice. Although the available data are limited, it is very likely that methotrexate is underused because its effectiveness is underestimated and its toxicity is overestimated. Both in induction therapy and in maintenance of remission, methotrexate is useful in Crohn's disease. When prescribed in combination with biologic agents, immunogenicity is less frequent and consequently long-term response could potentially be improved. There are few published studies, but several data suggest that methotrexate could also be useful in ulcerative colitis. Although myelotoxicity and liver toxicity are well known risks, methotrexate is a drug that is well tolerated in many patients, even in the long term.
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Affiliation(s)
- Fernando Gomollón
- Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, IIS Aragón, España Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD).
| | - Saioa Rubio
- Servicio de Aparato Digestivo, Hospital de Navarra, PamplonaEspaña
| | - Mara Charro
- Servicio de Aparato Digestivo, Hospital Royo Villanova, Zaragoza España
| | - Santiago García-López
- Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Zaragoza, España
| | - Fernando Muñoz
- Servicio de Aparato Digestivo, Hospital de León, León España
| | - Javier P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid España, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
| | - Eugeni Domènech
- Servicio de Aparato Digestivo, Hospital Germans Trías i Pujol, Badalona España, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
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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; 8:1179-207. [PMID: 24909831 DOI: 10.1016/j.crohns.2014.04.005] [Citation(s) in RCA: 826] [Impact Index Per Article: 75.1] [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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Abstract
BACKGROUND Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. METHODS Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. RESULTS Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001). CONCLUSIONS MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.
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Sobczak M, Fabisiak A, Murawska N, Wesołowska E, Wierzbicka P, Wlazłowski M, Wójcikowska M, Zatorski H, Zwolińska M, Fichna J. Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases. Pharmacol Rep 2014; 66:766-75. [PMID: 25149979 DOI: 10.1016/j.pharep.2014.04.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/29/2014] [Accepted: 04/09/2014] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic, relapsing disorders affecting gastrointestinal (GI) tract and associated with intestinal mucosa damage and inflammation. The principal therapeutic goals in IBD include control of the intestinal inflammation and treatment of the major symptoms, mainly abdominal pain and diarrhea. Current therapeutic strategies for IBD rely on the use of non-specific anti-inflammatory agents and immunosuppressive drugs (e.g. aminosalicylates, monoclonal antibodies, and antibiotics), which cause severe side effects, and - in a significant number of patients - do not induce long-term benefits. In this review, we summarize the epidemiology and the most important risk factors of IBD, including genetic, immunological and environmental. Our main focus is to discuss pharmacological targets for current and future treatments of IBD.
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Affiliation(s)
- Marta Sobczak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Natalia Murawska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Ewelina Wesołowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Paulina Wierzbicka
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marcin Wlazłowski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Wójcikowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Hubert Zatorski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Zwolińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
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Abstract
Increasing numbers of adolescents are being diagnosed with Crohn's disease or ulcerative colitis, the two main subtypes of inflammatory bowel disease. These young people face many short- and long-term challenges; one or more medical therapies may be required indefinitely; their disease may have great impact, in terms of their schooling and social activities. However, the management of adolescents with one of these incurable conditions needs to encompass more than just medical therapies. Growth, pubertal development, schooling, transition, adherence, and psychological well-being are all important aspects. A multidisciplinary team setting, catering to these components of care, is required to ensure optimal outcomes in adolescents with inflammatory bowel disease.
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Affiliation(s)
- J Bishop
- Paediatric Gastroenterology, Starship Children’s Hospital, Auckland, New Zealand
| | - DA Lemberg
- Department of Gastroenterology, Sydney Children’s Hospital, Sydney, Australia
| | - AS Day
- Department of Paediatrics, University of Otago (Christchurch), Christchurch, New Zealand
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Valentino PL, Church PC, Shah PS, Beyene J, Griffiths AM, Feldman BM, Kamath BM. Hepatotoxicity caused by methotrexate therapy in children with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2014; 20:47-59. [PMID: 24280876 DOI: 10.1097/01.mib.0000436953.88522.3e] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. METHODS We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. RESULTS Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%-18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%-9.5%), whereas 4.5% (95% CI 2.8%-7.2%) of patients required discontinuation. CONCLUSIONS Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.
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Affiliation(s)
- Pamela L Valentino
- 1Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 2Neonatal Intensive Care Unit, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Toronto, ON, Canada; and 4Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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Adjunctive treatment to antitumor necrosis factor in pediatric patients with refractory Crohn's disease. Curr Opin Pediatr 2013; 25:624-8. [PMID: 23995433 DOI: 10.1097/mop.0b013e328364df22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The use of antitumor necrosis factor (anti-TNF) agents to treat Crohn's disease in children has become quite common over the past decade. There are incomplete data to guide the clinician in choosing whether adjunctive therapy should be added to optimize response to these drugs. RECENT FINDINGS Addition of immunomodulators such as thiopurines or possibly methotrexate can increase anti-TNF drug levels, reduce the risk of antidrug antibodies, and improve response. This is tempered by the reports of younger patients developing hepato-splenic T-cell lymphoma while taking thiopurines with and without concomitant anti-TNF medications. The available data are reviewed including recent pediatric reports. SUMMARY The addition of immunomodulators to anti-TNF therapies can optimize their performance. Careful discussion of the risks and side-effects must be undertaken when considering this approach. Additional knowledge is required to stratify which children with inflammatory bowel disease need this approach, and/or who are at risk for significant complications.
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