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Zhao C, Wen S, Xu R, Wang K, Zhong Y, Huang D, Zhao B, Chen W. Oral delivery of ultra-small zwitterionic nanoparticles to overcome mucus and epithelial barriers for macrophage modulation and colitis therapy. Acta Biomater 2025; 196:399-409. [PMID: 39983856 DOI: 10.1016/j.actbio.2025.02.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/17/2025] [Accepted: 02/18/2025] [Indexed: 02/23/2025]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that poses significant therapeutic challenges due to the intestinal mucus and epithelial barriers. In this study, ultra-small zwitterionic nanoparticles (HC-CB NPs) is developed based on glutathione (GSH)-responsive hyperbranched polycarbonate to enhance the oral delivery of drugs and overcome these physiological barriers. HC-CB NPs demonstrate high colloidal stability across a wide range of pH environments and physiological fluids, preventing premature drug release within the gastrointestinal tract. The ultra-small sized HC-CB NPs demonstrate minimal mucin adsorption and effectively penetrate through the mucus layer, and the zwitterion surface further facilitate epithelial barrier crossing via the proton-assisted amino acid transporter 1 (PAT1) pathway. HC-CB NPs mediate enhanced macrophage uptake via monocarboxylate transporters (MCTs) pathway and ultimately improved therapy efficacy on colitis. The in vivo results reveal that FK506-loaded HC-CB NPs (HC-CB NPs@FK506) significantly reduce inflammatory markers (TNF-α, IL-6) and myeloperoxidase (MPO) levels, while promoting epithelial integrity by increasing E-cadherin expression. This study offers a promising approach to overcoming intestinal barriers in oral UC treatment, offering biocompatibility and potential for clinical translation. STATEMENT OF SIGNIFICANCE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that poses significant therapeutic challenges due to the intestinal mucus and epithelial barriers. This study explores an oral UC therapy using ultra-small zwitterionic nanoparticles (HC-CB NPs) constructed from GSH-responsive hyperbranched polycarbonate. Compared to existing strategies, HC-CB NPs demonstrate minimal mucin adsorption and effectively penetrate through the mucus layer, and the zwitterion surface further facilitate epithelial barrier crossing via the proton-assisted amino acid transporter 1 (PAT1) pathway. Additionally, HC-CB NPs mediate enhanced macrophage uptake via monocarboxylate transporters (MCTs) pathway, resulting in improved therapeutic efficacy. These findings underscore the potential of HC-CB NPs as a transformative platform for overcoming intestinal barriers in UC treatment.
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Affiliation(s)
- Changshun Zhao
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Suchen Wen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Rui Xu
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Ke Wang
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Yinan Zhong
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
| | - Dechun Huang
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China; Engineering Research Center for Smart Pharmaceutical Manufacturing Technologies, Ministry of Education, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Bingbing Zhao
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
| | - Wei Chen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China; Engineering Research Center for Smart Pharmaceutical Manufacturing Technologies, Ministry of Education, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
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Li R, Yang L. Research progress in the combined treatment of ulcerative colitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2025; 117:129-135. [PMID: 37073706 DOI: 10.17235/reed.2023.9444/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
In recent years, more and more drugs have been used in the treatment of ulcerative colitis, but the efficacy of monotherapy is limited, especially for patients with refractory moderate to severe ulcerative colitis (UC). Combination therapy is mainly used for patients with a poor response or partial efficacy of monotherapy and has become a new direction for exploring the treatment strategy of ulcerative colitis. Therefore, the authors review the combined treatment options of ulcerative colitis in the context of the existing literature and discuss considerations for the practical application of combination therapy, hoping to provide new ideas for clinicians in the treatment of ulcerative colitis.
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Affiliation(s)
- Rui Li
- Gastroenterology, China-Japan Union Hospital of Jilin University
| | - Lei Yang
- Gastroenterology, China-Japan Union Hospital of Jilin University, China
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Zhang D, Jiang L, Yu F, Yan P, Liu Y, Wu Y, Yang X. PepT1-targeted nanodrug based on co-assembly of anti-inflammatory peptide and immunosuppressant for combined treatment of acute and chronic DSS-induced ColitiS. Front Pharmacol 2024; 15:1442876. [PMID: 39211778 PMCID: PMC11357942 DOI: 10.3389/fphar.2024.1442876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory bowel diseases with limited therapeutic outcomes, is characterized by immune disorders and intestinal barrier dysfunction. Currently, the most medications used to cure IBD in clinic just temporarily induce and maintain remission with poor response rates and limited outcomes. Therefore, it is urgently necessary to develop an appropriate therapeutic candidate with preferable efficacy and less adverse reaction for curing IBD. METHODS Five groups of mice were utilized: control that received saline, DSS group (mice received 2.5% DSS or 4% DSS), KPV group (mice received KPV), FK506 group (mice received FK506) and NPs groups (mice received NPs). The effect of NP on the inflammatory factors of macrophage was evaluated using CCK-8, quantitative polymerase chain reaction (PCR), Elisa and Western blot (WB). Immunofluorescent staining revealed the targeting relationship between NP and Petp-1. Immunohistochemistry staining showed the effect of NP on tight junction proteins. Moreover, in vivo animal experiments confirmed that NPs reduced inflammatory levels in IBD. RESULTS AND DISCUSSION After administering with NPs, mice with DSS-induced acute or chronic colitis exhibited significant improvement in body weight, colon length, and disease activity index, decreased the level of the factors associated with oxidative stress (MPO, NO and ROS) and the inflammatory cytokines (TNF-α, IL-1β and IL-6), which implied that NPs could ameliorate murine colitis effectively. Furthermore, treating by NPs revealed a notable reduction of the expressions of CD68 and CD3, restoring the expression levels of tight junction proteins (Claudin-5, Occludin-1, and ZO-1) were significantly restored, surpassing those observed in the KPV and FK506 groups. which indicated that NPs can reduce inflammation and enhance epithelial barrier integrity by decreasing the infiltration of macrophages and T-lymphocytes. Collectively, those results demonstrated the effectively therapeutic outcome after using NPs in both acute and chronic colitis, suggesting that the newly co-assembled of NPs can be as a potential therapeutic candidate for colitis.
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Affiliation(s)
- Daifang Zhang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Longqi Jiang
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Fengxu Yu
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Pijun Yan
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yong Liu
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Ya Wu
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xi Yang
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Takatsu N, Hisabe T, Kishi M, Takeda T, Yasukawa S, Koga A, Kinjo K, Hirai F, Ueki T, Yao K. Thiopurine naivety at tacrolimus induction is a predictor of long-term remission in patients with intractable ulcerative colitis who responded to tacrolimus. J Gastroenterol Hepatol 2023; 38:52-60. [PMID: 36128954 DOI: 10.1111/jgh.16006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 08/21/2022] [Accepted: 09/07/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND The short-term efficacy of tacrolimus (Tac) for steroid-dependent and steroid-resistant refractory ulcerative colitis (UC) has been demonstrated; however, its long-term outcomes have not been well documented. Thus, this study aimed to clarify the long-term outcomes of patients who achieved Tac-induced remission and identify its predictors. METHODS This study included patients with moderate-to-severe active UC who started receiving Tac at our hospital between July 2004 and December 2016. Short-term treatment response was assessed using the Lichtiger index 3 months after starting Tac, and responding patients were further followed up to assess long-term outcomes. The primary endpoint was the relapse-free survival after Tac-induced remission, and the secondary endpoint was the identification of factors associated with relapse after Tac-induced remission. RESULTS The cumulative relapse-free survival rate at 10 years after Tac-induced remission was 33.2%. Multivariate analysis revealed that being thiopurine naïve at Tac induction was associated with the absence of relapse (hazard ratio: 0.45; 95% confidence interval: 0.22-0.92). CONCLUSIONS Approximately one-third of patients who achieved Tac-induced remission maintained long-term remission. Being thiopurine naïve at Tac induction was a predictor of the absence of relapse.
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Affiliation(s)
- Noritaka Takatsu
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Takashi Hisabe
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan.,Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Masahiro Kishi
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Teruyuki Takeda
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Shigeyoshi Yasukawa
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Akihiro Koga
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Ken Kinjo
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Toshiharu Ueki
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Kenshi Yao
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Fukuoka, Japan
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Sud S, Sachdeva S, Puri AS. Tacrolimus as rescue therapy for steroid-dependent/steroid-refractory ulcerative colitis: Experience from tertiary referral center in India. Indian J Gastroenterol 2021; 40:598-603. [PMID: 34971402 DOI: 10.1007/s12664-021-01185-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 04/19/2021] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Between 20% and 40% of patients with severe ulcerative colitis (UC) are either steroid-refractory UC (SRUC) or steroid-dependent UC (SDUC). Tacrolimus is an oral and relatively inexpensive drug, which has been extensively used in Japan for steroid-refractory and steroid-dependent disease. METHODS Patients diagnosed with SDUC/SRUC were treated with tacrolimus 0.05-0.1 mg/kg in this prospective study. Clinical Mayo score (CMS) and UC Endoscopic Index of Severity (UCEIS) were evaluated prior to starting the drug and subsequently after 8 weeks. 5-Aminosalicylic acid agents (5-ASA) and immunomodulators were continued if the patients were previously on these drugs. Clinical response at 8 weeks was defined as decrease in CMS by at least 3 points. Clinical remission was defined as CMS ≤2 and combined remission as CMS≤2 with UCEIS <3. RESULTS Fifty-two patients (29 males) with a mean age of 35.1± 12.8 years with predominantly E3 disease (71%) were prospectively evaluated in this study. SDUC and SRUC were diagnosed in 31 and 21 patients, respectively. Seven failed treatment within 8 weeks, four were subjected to surgery, and 3 were switched to infliximab. Forty-two patients continued tacrolimus for 8 weeks. Mean CMS and UCEIS prior to starting tacrolimus were 6 ± 1.1 and 4.8 ± 1.1, respectively. At 8 weeks, median CMS and UCEIS decreased to 2.6 ± 1.7 and 2.7 ± 1.3, respectively. Clinical response was documented in 29 patients (56%) at week 8 whereas clinical remission was seen in 25 patients (48%). Combined clinical and endoscopic remissions were seen in 18 patients (35%). Except for a single patient who developed reversible renal dysfunction, no other adverse event was observed. CONCLUSION Our results show that tacrolimus is effective in inducing a clinical response in 56% of patients with SDUC and SRUC. In view of its low cost and safety profile, it may be considered first-line therapy for SDUC/SRUC.
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Affiliation(s)
- Sukrit Sud
- Department of Gastroenterology, G B Pant Institute of Postgraduate Medical Education and Research, New Delhi 110 002, India. .,Medanta -The Medicity Hospital, Gurugram, 122 006, India.
| | - Sanjeev Sachdeva
- Department of Gastroenterology, G B Pant Institute of Postgraduate Medical Education and Research, New Delhi 110 002, India.,Medanta -The Medicity Hospital, Gurugram, 122 006, India
| | - Amarender Singh Puri
- Department of Gastroenterology, G B Pant Institute of Postgraduate Medical Education and Research, New Delhi 110 002, India.,Medanta -The Medicity Hospital, Gurugram, 122 006, India
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Manzini R, Schwarzfischer M, Atrott K, Laimbacher A, Lang S, Wawrzyniak M, Rickenbacher A, Turina M, Hruz P, Lissner D, Siegmund B, Rogler G, Scharl M, Spalinger MR. Combination of Vedolizumab With Tacrolimus Is More Efficient Than Vedolizumab Alone in the Treatment of Experimental Colitis. Inflamm Bowel Dis 2021; 27:1986-1998. [PMID: 33847343 DOI: 10.1093/ibd/izab063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Vedolizumab is a widely used and safe therapy in inflammatory bowel disease, particularly in ulcerative colitis (UC), making it a promising candidate for enhanced efficacy by combining it with additional immunomodulatory medications. In this study, we studied the impact of vedolizumab monotreatment vs vedolizumab coadministration with other immunomodulatory drugs on intestinal inflammation and intestinal immune cells in vivo. METHODS Colon tissue from human patients with UC with active disease or in remission with or without vedolizumab treatment was stained by immunohistochemistry. We reconstituted NOD-SCID-SGM3 mice with human CD34+ cells and treated them with dextran sodium sulfate to induce acute colitis. Mice were treated with vedolizumab alone, or in combination with tacrolimus, ozanimid, or tofacitinib. RESULTS Vedolizumab reduced the number of CD3+ T cells and CD68+ monocytes/macrophages in the colon of patients with UC with active disease. Vedolizumab moderately decreased immune cell numbers in acute dextran sodium sulfate-induced colitis. The combination of vedolizumab with tacrolimus further reduced the number of infiltrating CD3+ T cells and CD68+ monocytes/macrophages and was superior in ameliorating intestinal inflammation when compared to vedolizumab monotreatment. In contrast, cotreatment using vedolizumab with ozanimod or tofacitinib had no additive effect. CONCLUSIONS Our data show that vedolizumab reduces the number of innate and adaptive immune cells in the mucosa of patients with UC. Further, the combination of vedolizumab with tacrolimus was more efficient to reduce immune cell numbers and to increase therapeutic efficacy than vedolizumab monotreatment. This finding indicates that combination treatment using these two drugs may be beneficial for patients who do not respond to vedolizumab monotherapy.
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Affiliation(s)
- Roberto Manzini
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Andrea Laimbacher
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
| | - Andreas Rickenbacher
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Matthias Turina
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Petr Hruz
- Clarunis Universitäres Bauchzentrum Basel, University Hospital Basel, Basel, Switzerland
| | - Donata Lissner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin. Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Berlin,Germany
| | - Britta Siegmund
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin. Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Berlin,Germany
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland.,Zurich Center for Integrated Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland.,Zurich Center for Integrated Human Physiology, University of Zurich, Zurich, Switzerland
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,Switzerland
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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Cai X, Wang X, He M, Wang Y, Lan M, Zhao Y, Gao F. Colon-targeted delivery of tacrolimus using pH-responsive polymeric nanoparticles for murine colitis therapy. Int J Pharm 2021; 606:120836. [PMID: 34217824 DOI: 10.1016/j.ijpharm.2021.120836] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/03/2021] [Accepted: 06/25/2021] [Indexed: 12/14/2022]
Abstract
The present study aimed at constructing an oral nanoparticle delivery system loaded with tacrolimus (FK506) for effective treatment of inflammatory bowel disease. A FK506/HP-β-CD inclusion compound was prepared by grinding to increase drug solubility. To address the side- effects in non-target organs and systemic toxicity of FK506, pH-responsive Eudragit S100 (ES100) and hyaluronic acid (HA) with high affinity to CD44 receptor were adsorbed onto the surface of chitosan (CS) nanoparticles loaded with FK506/HP-β-CD through electrostatic interactions to obtain FK506@ES100/HA/CS/HP-β-CD nanoparticles (FK506@EHCh NPs). Caco-2 cells and Raw 264.7 macrophages were used to confirm the lack of cytotoxicity and good uptake ability of the newly generated nanoparticles. FK506@EHCh NPs significantly suppressed secretion of TNF-α, IL-1β and IL-6 by LPS-activated Raw 264.7 macrophages. A dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) murine model was established to further confirm the colon targeting and in vivo efficacy of oral IR-775@EHCh NPs. Based on the collective results, we conclude that packaging FK506 into active targeting nanocarriers sensitive to pH facilitates concentration of the drug within the sites of intestinal inflammation and improves the drug levels in target tissues, thus avoiding systemic side-effects and improving efficacy. In view of the promising results obtained in this study, the potential of EHCh nanoparticles for drug delivery and targeted treatment of inflammatory bowel disease warrants further investigation.
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Affiliation(s)
- Xiaoran Cai
- Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaolei Wang
- Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Muye He
- Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yan Wang
- Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Minbo Lan
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China
| | - Yuzheng Zhao
- Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, China
| | - Feng Gao
- Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China.
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Ishida N, Miyazu T, Tamura S, Tani S, Yamade M, Iwaizumi M, Hamaya Y, Osawa S, Furuta T, Sugimoto K. Early serum albumin changes in patients with ulcerative colitis treated with tacrolimus will predict clinical outcome. World J Gastroenterol 2021; 27:3109-3120. [PMID: 34168412 PMCID: PMC8192282 DOI: 10.3748/wjg.v27.i22.3109] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/11/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Oral tacrolimus is a therapeutic agent for moderate to severe steroid-dependent or resistant ulcerative colitis (UC), but remission induction is difficult, and it is necessary to treat the patient while considering the next treatment. AIM To examine serum albumin (Alb) level as a prognostic factor for the therapeutic effect of tacrolimus in clinical practice. METHODS Forty-seven patients with UC treated with tacrolimus at our institution were divided into remission and failure groups (colectomy or switch to biologics), and the biological data at the start of observation and at weeks 1 and 2 were retrospectively examined. Kaplan-Meier and multivariate analyses were performed using Alb as a prognostic factor in UC treatment. RESULTS During the three months observed, 17 (36.2%) patients failed treatment with tacrolimus. A comparison between the failure and remission groups showed a significant difference only in Alb in week 2, and in the week 2/week 0 Alb ratio, which showed the rate of change in Alb. The cut-off value of the week 2/week 0 Alb ratio that predicted failure was 1, and its area under the curve was 0.751 (95%CI: 0.604-0.898). In the Kaplan-Meier analysis, a week 2/week 0 Alb ratio ≤ 1 had a significantly higher failure rate than that of > 1; Cox proportional hazard regression analysis also showed that a week 2/week 0 Alb ratio ≤ 1 was an independent prognostic factor for failure within 3 mo after the start of tacrolimus treatment. CONCLUSION A week 2/week 0 Alb ratio ≤ 1 predicts failure within 3 mo of tacrolimus administration for UC. High failure risk exists with week 2 Alb values ≤ 1 on admission.
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Affiliation(s)
- Natsuki Ishida
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Takahiro Miyazu
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Satoshi Tamura
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University of School of Medicine, Hamamatsu 43131, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan
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10
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Lee S, Clark-Snustad K. Patient with Fistulizing Crohn's Disease with Nonresponse to Infliximab Subsequently Responds to Infliximab After Short-term Addition of Tacrolimus. Inflamm Bowel Dis 2021; 27:e20-e22. [PMID: 33119736 DOI: 10.1093/ibd/izaa260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Scott Lee
- University of Washington, Division of Gastroenterology
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11
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Ng SC, Mak JWY, Pal P, Banerjee R. Optimising management strategies of inflammatory bowel disease in resource-limited settings in Asia. Lancet Gastroenterol Hepatol 2020; 5:1089-1100. [PMID: 33181088 DOI: 10.1016/s2468-1253(20)30298-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 05/16/2020] [Accepted: 05/20/2020] [Indexed: 12/16/2022]
Abstract
Over the 21st century, inflammatory bowel disease (IBD) has become a global disease with increasing prevalence reported in the Asian subcontinent as a result of rapid urbanisation, industrialisation, and westernisation of lifestyles. Although rates of surgery have shown a temporal decrease globally because of the increasing availability of new drugs and early initiation of effective therapy, health-care costs associated with IBD have continued to rise. The increase in IBD prevalence in resource-limited countries poses a substantial health-care burden. Drugs are not universally accessible or available. An optimised and practical management strategy of IBD in resource-limited countries in Asia is urgently needed. Special consideration should be made to balance the risk of undertreatment (and suboptimal disease control) because of financial constraints with the risk of overtreatment, which is associated with side-effects and costly therapeutics. In this Series paper, we summarise the current approach in optimising conventional therapies, use of other therapies, and de-escalation of biologics in low-resource settings in Asia. The long-term objective is to strive for more effective and affordable therapies with sustained durability of benefit.
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Affiliation(s)
- Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Partha Pal
- IBD Centre, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rupa Banerjee
- IBD Centre, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
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12
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Wu B, Tong J, Ran Z. Tacrolimus Therapy in Steroid-Refractory Ulcerative Colitis: A Review. Inflamm Bowel Dis 2020; 26:24-32. [PMID: 30980713 DOI: 10.1093/ibd/izz068] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel diseases are known for a chronic inflammatory process of the gastrointestinal tract and include Crohn's disease and ulcerative colitis (UC). Patients who are dependent on or resistant to corticosteroids account for about 20% of severe UC patients. Tacrolimus is a calcineurin inhibitor that has recently been used in the treatment of steroid-refractory ulcerative colitis. Tacrolimus has been demonstrated to have remarkable therapeutic efficacy in UC patients, without increased risk of severe adverse effects such as induction of remission and maintenance therapy. This article reviews the mechanism of action, pharmacogenetics, efficacy, and safety of tacrolimus for patients with steroid-refractory ulcerative colitis.
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Affiliation(s)
- Biyu Wu
- Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Jinglu Tong
- Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Zhihua Ran
- Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
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13
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Iida T, Nojima M, Nakase H. Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis. Dig Dis Sci 2019; 64:2945-2954. [PMID: 30982208 DOI: 10.1007/s10620-019-05619-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 04/08/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.
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Affiliation(s)
- Tomoya Iida
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
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14
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Christensen B, Gibson P, Micic D, Colman RJ, Goeppinger SR, Kassim O, Yarur A, Weber CR, Cohen RD, Rubin DT. Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2019; 17:486-493. [PMID: 29751166 PMCID: PMC7034423 DOI: 10.1016/j.cgh.2018.04.060] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 04/10/2018] [Accepted: 04/29/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors. METHODS We collected data on patients with CD (n = 9) or UC (n = 11) who began treatment with vedolizumab from May 20, 2014, through March 30, 2015, and received calcineurin inhibitors (tacrolimus or cyclosporin) during the first 12 months of vedolizumab therapy. Clinical activity scores and inflammatory markers were measured at baseline and at weeks 14, 30, and 52 of vedolizumab treatment. Clinical remission was defined as a Harvey-Bradshaw index score ≤4 or short clinical colitis activity index score ≤2; steroid-free clinical remission was defined as clinical remission without corticosteroids. RESULTS By week 14 of treatment, 44% of the patients with CD and 55% of the patients with UC achieved steroid-free clinical remission; after 52 weeks of treatment, 33% of the patients with CD and 45% of the patients with UC were in steroid-free clinical remission. Seven patients received salvage therapy with a calcineurin inhibitor after primary nonresponse to vedolizumab-1 of the 2 patients with UC and 2 of 5 patients with CD stopped taking the calcineurin inhibitors and achieved steroid-free remission at week 52. In total, 16 patients (59%) received 52 weeks of treatment with vedolizumab. Three serious adverse events were associated with calcineurin inhibitors. CONCLUSIONS Combination therapy of vedolizumab with either cyclosporin or tacrolimus is effective and safe at inducing and maintaining clinical remission in patients with CD and UC with up to 52 weeks of follow-up evaluation. Larger studies of the ability of calcineurin inhibitors to induce remission in patients on vedolizumab are warranted.
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Affiliation(s)
- Britt Christensen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois; Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Australia.
| | - Peter Gibson
- Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia
| | - Dejan Micic
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | - Ruben J Colman
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | - Sarah R Goeppinger
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | - Olufemmi Kassim
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | - Andres Yarur
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | | | - Russell D Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Il, USA
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15
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Fanucchi S, Fok ET, Dalla E, Shibayama Y, Börner K, Chang EY, Stoychev S, Imakaev M, Grimm D, Wang KC, Li G, Sung WK, Mhlanga MM. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet 2018; 51:138-150. [PMID: 30531872 DOI: 10.1038/s41588-018-0298-2] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 10/30/2018] [Indexed: 12/22/2022]
Abstract
Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene-priming lncRNAs (IPLs). We show that the prototypical IPL, UMLILO, acts in cis to direct the WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) complex across the chemokine promoters, facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. Training mediated by β-glucan epigenetically reprograms immune genes by upregulating IPLs in manner dependent on nuclear factor of activated T cells. The murine chemokine topologically associating domain lacks an IPL, and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine topologically associating domain in mouse macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.
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Affiliation(s)
- Stephanie Fanucchi
- Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,BTRI, CSIR Biosciences, Pretoria, South Africa
| | - Ezio T Fok
- Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,BTRI, CSIR Biosciences, Pretoria, South Africa
| | - Emiliano Dalla
- Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Department of Medicine, Università degli Studi di Udine, Udine, Italy
| | - Youtaro Shibayama
- Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kathleen Börner
- Department of Infectious Diseases/Virology, BioQuant Center, Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Partner Site, German Center for Infection Research (DZIF), Heidelberg, Germany
| | - Erin Y Chang
- Department of Dermatology, Stanford University, Stanford, CA, USA
| | - Stoyan Stoychev
- Biomedical Technologies Group, CSIR Biosciences, Pretoria, South Africa
| | - Maxim Imakaev
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Boston, MA, USA
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, BioQuant Center, Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Partner Site, German Center for Infection Research (DZIF), Heidelberg, Germany.,Cluster of Excellence CellNetworks, Heidelberg, Germany
| | - Kevin C Wang
- Department of Dermatology, Stanford University, Stanford, CA, USA
| | - Guoliang Li
- College of Informatics, Huazhong Agricultural University, Wuhan, China
| | - Wing-Kin Sung
- School of Computing, National University of Singapore, Singapore, Singapore.,Genome Institute of Singapore, Singapore, Singapore
| | - Musa M Mhlanga
- Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal.
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16
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Amine L, Abdelgadir IS, Neves K, Elawad M, Hassan A, Akobeng AK. Tacrolimus for induction therapy in active Crohn's disease. Hippokratia 2018. [DOI: 10.1002/14651858.cd013142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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17
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Lawrance IC, Baird A, Lightower D, Radford-Smith G, Andrews JM, Connor S. Efficacy of Rectal Tacrolimus for Induction Therapy in Patients With Resistant Ulcerative Proctitis. Clin Gastroenterol Hepatol 2017; 15:1248-1255. [PMID: 28286194 DOI: 10.1016/j.cgh.2017.02.027] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/22/2017] [Accepted: 02/24/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Resistant ulcerative proctitis can be extremely difficult to manage. Topically administered tacrolimus, however, may be effective in difficult-to-treat proctitis. This was a randomized, double-blind, placebo-controlled induction trial of rectal tacrolimus in patients with active ulcerative colitis. METHODS Eleven patients received rectal tacrolimus (0.5 mg/mL), and 10 placebo, for 8 weeks. The primary endpoint was clinical response by using the Mayo Clinic score. RESULTS A planned interim analysis after 20 patients had completed the study demonstrated highly significant differences between the groups and the study was closed because of ethical considerations with patients already recruited allowed to complete the study. The primary endpoint was met in 8 of 11 patients receiving rectal tacrolimus and 1 of 10 patients receiving placebo (73% vs 10%; P = .004). Of the secondary endpoints, 5 patients with rectal tacrolimus achieved clinical remission compared with none receiving placebo (45% vs 0%; P = .015). Mucosal healing at Week 8 was achieved in 8 patients receiving rectal tacrolimus compared with 1 (73% vs 10%) receiving placebo (P = .004). The Inflammatory Bowel Disease Questionnaire increased ≥16 points over baseline in 5 of the tacrolimus and 2 (45% vs 20%) of the placebo patients (P = .36). Finally, the average partial Mayo score was numerically lower in the tacrolimus-treated group compared with placebo at Week 2 (4.3 ± 0.74 vs 5.8 ± 0.64; P = .15) and Week 4 (3.7 ± 0.96 vs 5.8 ± 0.6; P = .08) but was significantly lower at Week 8 (3.3 ± 1.2 vs 6.7 ± 0.62; P = .01). There were no safety issues identified with rectal tacrolimus use. CONCLUSIONS Rectal tacrolimus was more effective than placebo for induction of a clinical response, clinical remission, and mucosal healing in resistant ulcerative proctitis (Clinicaltrials.gov registration: NCT01418131).
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Affiliation(s)
- Ian C Lawrance
- Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, WA, Australia; Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, WA, Australia.
| | - Angela Baird
- Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, WA, Australia
| | - Daniel Lightower
- Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, WA, Australia
| | - Graham Radford-Smith
- IBD Research Group, QIMR Berghofer Medical Research Institute, University of Queensland School of Medicine, Brisbane, Queensland, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Jane M Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia; University of Adelaide, School of Medicine, SA, Australia
| | - Susan Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, NSW, Australia; South Western Sydney Clinical School, University of NSW Medicine, Sydney, NSW, Australia; Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, UNSW Australia, Sydney, NSW, Australia
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18
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Chang S, Hanauer S. Optimizing pharmacologic management of inflammatory bowel disease. Expert Rev Clin Pharmacol 2017; 10:595-607. [DOI: 10.1080/17512433.2017.1318062] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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19
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Lasa J, Olivera P. EFFICACY OF TACROLIMUS FOR INDUCTION OF REMISSION IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:167-172. [PMID: 28327826 DOI: 10.1590/s0004-2803.201700000-15] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 12/26/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is evidence that shows that calcineurin inhibitors may be useful for the treatment of severe ulcerative colitis. However, evidence regarding the efficacy of tacrolimus for remission induction in this setting is scarce. OBJECTIVE To develop a systematic review on the existing evidence regarding the clinical efficacy of tacrolimus for the induction of remission in patients with moderate-to-severe ulcerative colitis. METHODS A literature search was undertaken from 1966 to August 2016 using MEDLINE, Embase, LILACS and the Cochrane Library. The following MeSH terms were used: "Inflammatory Bowel Diseases" or "Ulcerative Colitis" and "Calcineurin Inhibitors" or "Tacrolimus" or "FK506". Studies performed in adult ulcerative colitis patients that evaluated the clinical efficacy of tacrolimus for the induction of remission were considered for revision. A meta-analysis was performed with those included studies that were also placebo-controlled and randomized. Clinical response as well as clinical remission and mucosal healing were evaluated. RESULTS Overall, 755 references were identified, from which 22 studies were finally included. Only two of them were randomized, placebo-controlled trials. A total of 172 patients were evaluated. A significantly lower risk of failure in clinical response was found for tacrolimus versus placebo [RR 0.58 (0.45-0.73)]; moreover, a lower risk of failure in the induction of remission was also found versus placebo [RR 0.91 (0.82-1)]. CONCLUSION Tacrolimus seems to be a valid therapeutic alternative for the induction of remission in patients with moderate-to-severe ulcerative colitis.
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Affiliation(s)
- Juan Lasa
- Gastroenterology Section, Internal Medicine Department. Centro de Educacion Medica e Investigaciones Clinicas Norberto Quirno (CEMIC). Buenos Aires, Argentina
| | - Pablo Olivera
- Gastroenterology Section, Internal Medicine Department. Centro de Educacion Medica e Investigaciones Clinicas Norberto Quirno (CEMIC). Buenos Aires, Argentina
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20
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Regueiro MD, Greer JB, Hanauer SB. Established Management Paradigms in IBD: Treatment Targets and Therapeutic Tools. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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21
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Vlachos C, Gaitanis G, Katsanos KH, Christodoulou DK, Tsianos E, Bassukas ID. Psoriasis and inflammatory bowel disease: links and risks. PSORIASIS-TARGETS AND THERAPY 2016; 6:73-92. [PMID: 29387596 PMCID: PMC5683131 DOI: 10.2147/ptt.s85194] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Psoriasis and the spectrum of inflammatory bowel diseases (IBD) are chronic, inflammatory, organotropic conditions. The epidemiologic coexistence of these diseases is corroborated by findings at the level of disease, biogeography, and intrafamilial and intrapatient coincidence. The identification of shared susceptibility loci and DNA polymorphisms has confirmed this correlation at a genetic level. The pathogenesis of both diseases implicates the innate and adaptive segments of the immune system. Increased permeability of the epidermal barrier in skin and intestine underlies the augmented interaction of allergens and pathogens with inflammatory receptors of immune cells. The immune response between psoriasis and IBD is similar and comprises phagocytic, dendritic, and natural killer cell, along with a milieu of cytokines and antimicrobial peptides that stimulate T-cells. The interplay between dendritic cells and Th17 cells appears to be the core dysregulated immune pathway in all these conditions. The distinct similarities in the pathogenesis are also reflected in the wide overlapping of their therapeutic approaches. Small-molecule pharmacologic immunomodulators have been applied, and more recently, biologic treatments that target proinflammatory interleukins have been introduced or are currently being evaluated. However, the fact that some treatments are quite selective for either skin or gut conditions also highlights their crucial pathophysiologic differences. In the present review, a comprehensive comparison of risk factors, pathogenesis links, and therapeutic strategies for psoriasis and IBD is presented. Specific emphasis is placed on the role of the immune cell species and inflammatory mediators participating in the pathogenesis of these diseases.
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Affiliation(s)
| | | | - Konstantinos H Katsanos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Epameinondas Tsianos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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22
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Abstract
Despite recent therapeutic advances, patients with Crohn's disease (CD) continue to experience high recurrence with cumulative structural damage and ultimate loss of nutritional autonomy. With short bowel syndrome, strictures, and enteric fistulae being the underlying pathology, CD is the second common indication for home parenteral nutrition (HPN). With development of intestinal failure, nutritional management including HPN is required as a rescue therapy. Unfortunately, some patients do not escape the HPN-associated complications. Therefore, the concept of gut rehabilitation has evolved as part of the algorithmic management of these patients, with transplantation being the ultimate life-saving therapy. With type 2 intestinal failure, comprehensive rehabilitative measures including nutritional care, pharmacologic manipulation, autologous reconstruction, and bowel lengthening is often successful, particularly in patients with quiescent disease. With type 3 intestinal failure, transplantation is the only life-saving treatment for patients with HPN failure and intractable disease. With CD being the second common indication for transplantation in adults, survival outcome continues to improve because of surgical innovation, novel immunosuppression, and better postoperative care. Despite being a rescue therapy, the procedure has achieved survival rates similar to other solid organs, and comparable to those who continue to receive HPN therapy. With similar technical, immunologic, and infectious complications, survival is similar in the CD and non-CD recipients. Full nutritional autonomy is achievable in most survivors with better quality of life and long-term cost-effectiveness. CD recurrence is rare with no impact on graft function. Further progress is anticipated with new insights into the pathogenesis of CD and mechanisms of transplant tolerance.
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23
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Schmidt KJ, Müller N, Dignass A, Baumgart DC, Lehnert H, Stange EF, Herrlinger KR, Fellermann K, Büning J. Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues. J Crohns Colitis 2016; 10:31-7. [PMID: 26419459 DOI: 10.1093/ecco-jcc/jjv175] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 09/02/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.
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Affiliation(s)
- K J Schmidt
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - N Müller
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - A Dignass
- Department of Internal Medicine I, Agaplesion Markus Hospital, Frankfurt, Germany
| | - D C Baumgart
- Department of Gastroenterology and Hepatology, Charite Medical School, Humboldt University of Berlin, Berlin, Germany
| | - H Lehnert
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - E F Stange
- Department of Gastroenterology, Hepatology and Endocrinology, Robert Bosch Hospital, Stuttgart, Germany
| | - K R Herrlinger
- Department of Internal Medicine I, Asklepios Klinik Nord, Hamburg, Germany
| | - K Fellermann
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - J Büning
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
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Rodríguez-Lago I, Merino O, Nantes Ó, Muñoz C, Aguirre U, Cabriada JL. Previous exposure to biologics and C-reactive protein are associated with the response to tacrolimus in inflammatory bowel disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2016; 108:550-7. [DOI: 10.17235/reed.2016.4447/2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Matsuoka K, Saito E, Fujii T, Takenaka K, Kimura M, Nagahori M, Ohtsuka K, Watanabe M. Tacrolimus for the Treatment of Ulcerative Colitis. Intest Res 2015; 13:219-26. [PMID: 26130996 PMCID: PMC4479736 DOI: 10.5217/ir.2015.13.3.219] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 05/06/2014] [Accepted: 05/06/2014] [Indexed: 02/07/2023] Open
Abstract
Tacrolimus is a calcineurin inhibitor used for the treatment of corticosteroid-refractory ulcerative colitis (UC). Two randomized controlled trials and a number of retrospective studies have assessed the therapeutic effect of tacrolimus in UC patients. These studies showed that tacrolimus has excellent short-term efficacy in corticosteroid-refractory patients, with the rates of clinical response ranging from 61% to 96%. However, the long-term prognosis of patients treated with tacrolimus is disappointing, and almost 50% of patients eventually underwent colectomy in long-term follow-up. Tacrolimus can achieve mucosal healing in 40-50% of patients, and this is associated with a favorable long-term prognosis. Anti-tumor necrosis factor (TNF)-α antibodies are another therapeutic option in corticosteroid-refractory patients. A prospective head-to-head comparative study of tacrolimus and infliximab is currently being performed to determine which treatment is more effective in corticosteroid-refractory patients. Several retrospective studies have demonstrated that switching between tacrolimus and anti-TNF-α antibody therapy was effective in patients who were refractory to one of the treatments. Most adverse events of tacrolimus are mild; however, opportunistic infections, especially pneumocystis pneumonia, are the most important adverse events, and these should be carefully considered during treatment. Several issues on tacrolimus treatment in UC patients remain unsolved (e.g., use of tacrolimus as remission maintenance therapy). Further controlled studies are needed to optimize the use of tacrolimus for the treatment of UC.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Takenaka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Maiko Kimura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Lawrance IC. Early investigational TNF receptor antagonists for the treatment of ulcerative colitis. Expert Opin Investig Drugs 2015; 24:761-8. [PMID: 25719407 DOI: 10.1517/13543784.2015.1020371] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Ulcerative colitis (UC) is a life-long, immunologically mediated condition that results from an inappropriate activation of the mucosal immune system by intestinal luminal antigens in genetically susceptible individuals. TNF-α is a pro-inflammatory cytokine central to UC pathogenesis. AREAS COVERED This review examines the evidence for the use of the anti-TNF (αTNF) medications infliximab, adalimumab, certolizumab and golimumab in the management of UC. It highlights the newer biosimilar agents that are becoming available and the early stage investigation of an orally administered αTNF agent. EXPERT OPINION αTNF therapy is effective but only in a proportion of UC patients. As there is now strong evidence that UC is not just a single disease but a series of phenotypes with distinct genetic, serological and environmental aspects, understanding the heterogeneity of the innate immunological response in UC could allow for better targeted patient management. Identifying differences in the efficacy of the various αTNF agents is difficult as there are no head-to-head studies, but only infliximab has proven clinical efficacy in the management of acute severe colitis. Biosimilars to the αTNF agents are now available and with the added competition, medications costs should fall allowing for greater patient access.
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Affiliation(s)
- Ian C Lawrance
- University of Western Australia, Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, Fiona Stanley Hospital , Murdoch, WA , Australia
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Minami N, Yoshino T, Matsuura M, Koshikawa Y, Yamada S, Toyonaga T, Madian A, Honzawa Y, Nakase H. Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study. BMJ Open Gastroenterol 2015; 2:e000021. [PMID: 26462273 PMCID: PMC4599165 DOI: 10.1136/bmjgast-2014-000021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 12/13/2014] [Accepted: 12/26/2014] [Indexed: 12/18/2022] Open
Abstract
Objective Treatment of severe ulcerative colitis (UC) is challenging. Although the efficacy of tacrolimus (TAC) and infliximab (IFX) have been evaluated in patients with severe UC, the safety and efficacy levels of sequential therapies (TAC→IFX/IFX→TAC) in these patients remain unclear. The aim of this study was to assess short-term and long-term outcomes in patients with severe UC treated with TAC and IFX. Methods From October 2001 to February 2014, 29 patients with consecutive severe UC treated with TAC or IFX were retrospectively evaluated. Median follow-up duration was 27 months (range 0.5–118 months). The primary end point was short-term outcomes at 8 weeks after induction of TAC (TAC group, n=22) or IFX (IFX group, n=7). The secondary end point included long-term outcomes and colectomy-free survival. The clinical response was evaluated based on a partial Mayo score. Results The clinical remission (CR) rate at 8 weeks in the TAC and IFX groups was 63.6% and 71.4%, respectively. In 13 of the 29 patients (10 in the TAC group, 3 in the IFX group), sequential therapies were used in their clinical courses. In 9 of these 13 patients (6 in the TAC group, 3 in the IFX group), CR was achieved and maintained by sequential therapies. Overall cumulative colectomy-free survival was 79.3% at 118 months. Conclusions TAC and IFX had similar effects on remission induction in patients with severely active UC. Sequential therapies could rescue patients with UC who failed initial treatment with TAC or IFX. In clinical practice, sequential therapies might be deliberately performed.
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Affiliation(s)
- Naoki Minami
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Takuya Yoshino
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Yorimitsu Koshikawa
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Satoshi Yamada
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Takahiko Toyonaga
- The Third Department of Internal Medicine , Kansai Medical University , Hirakata , Japan
| | - Ali Madian
- Department of Internal Medicine, Faculty of Medicine , Al-Azhar University , Cairo , Egypt
| | - Yusuke Honzawa
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
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Naito T, Shiga H, Endo K, Kuroha M, Kakuta Y, Kinouchi Y, Shimosegawa T. De novo Crohn's disease following orthotopic liver transplantation: a case report and literature review. Intern Med 2015; 54:199-204. [PMID: 25743012 DOI: 10.2169/internalmedicine.54.3156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The development of de novo Crohn's disease (CD) after orthotopic liver transplantation (OLT) is rare, possibly due to the continuous use of immunosuppressive treatment. Although several cases of CD following OLT have been reported worldwide, there are currently so such cases in Japan. We herein report the case of a patient who newly developed CD after undergoing OLT for congenital biliary atresia. The patient subsequently underwent ileocecal resection and has since maintained clinical remission. This is the first report of this condition in Japan. We also review the literature concerning cases of de novo inflammatory bowel disease (IBD) developing after OLT, and discuss the causes of and role of immunosuppressive agents in treating IBD.
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Affiliation(s)
- Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
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Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use. Inflamm Bowel Dis 2014; 20:2151-6. [PMID: 25029618 DOI: 10.1097/mib.0000000000000130] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice.
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Lawrance IC. What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails? World J Gastroenterol 2014; 20:1248-1258. [PMID: 24574799 PMCID: PMC3921507 DOI: 10.3748/wjg.v20.i5.1248] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/05/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.
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