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Alqadi R, Alqumia A, Alhomoud IS, Alhowail A, Aldubayan M, Mohammed HA, Alhmoud H, Khan RA. Cyclosporine: Immunosuppressive effects, entwined toxicity, and clinical modulations of an organ transplant drug. Transpl Immunol 2025; 88:102147. [PMID: 39549927 DOI: 10.1016/j.trim.2024.102147] [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: 07/21/2024] [Revised: 11/10/2024] [Accepted: 11/10/2024] [Indexed: 11/18/2024]
Abstract
The discovery and use of cyclosporine since its inception into the clinics in the '70s and up have played a crucial role in advancing transplant therapy, and containment of the immune-based rejections. The drug has improved the high rates of acute rejections and has supported early graft survival. However, the long-term survival of renal allografts is still less prevalent, and an in-depth analysis, as well as reported findings led us to believe that there is a chronic irreversible component to the drug, that is tackled through its metabolites, and that causes toxicity, which has led to new therapies, including monoclonal antibody-based medications. A recap of the immunosuppressive effects, and entwined toxicity of the drug, now relegated primarily to bone marrow early transplants, is being overviewed for the past protocols that were used to minimize, and avoid, or use this calcineurin inhibitor class of drug, cyclosporine, in combination with other drugs. The current review circumvents the cyclosporine's mechanism of action, pathophysiology, cytochrome roles, and other factors associated with acute and chronic toxicity developments. The review also attempts to find conclusive strategies reported in the recent studies to avoid its toxic side effects, and develop a safe-use strategy for the drug. Gastrointestinal decontamination, supporting the airway, monitoring for signs of respiratory insufficiency, monitoring for severe reactions, such as seizures, need for administration of oxygen, and avoiding the administration of drugs, that increase the blood levels of the cyclosporine, are beneficial interventions, when encountering cyclosporine toxicity cases. The constrained therapeutic outcomes have also led to redesign, and making use of combined formulations to reassess the pharmacokinetics of the drug.
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Affiliation(s)
- Razan Alqadi
- Department of Pharmacy, King Saud Hospital, Unaizah, Qassim 56249, Saudi Arabia
| | - Amal Alqumia
- Department of Pharmacy, King Fahd Specialist Hospital, Buraydah, Qassim 52719, Saudi Arabia
| | - Ibrahim S Alhomoud
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Ahmad Alhowail
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Maha Aldubayan
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Hussam Alhmoud
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Riaz A Khan
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia.
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2
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Amara S, Pasumarthi A, Parikh N, Kodali N, Lebwohl M, Monks G. Psoriasis management tree based on comorbidity. Int J Dermatol 2025; 64:229-245. [PMID: 39420121 DOI: 10.1111/ijd.17497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 10/19/2024]
Abstract
Psoriasis, a common chronic inflammatory skin disorder, encompasses various subtypes, including guttate, pustular, erythrodermic, and the most common type, plaque psoriasis. Irrespective of the subtype, psoriasis can manifest with multisystemic presentations, including psoriatic arthritis, metabolic disorders, cardiovascular disease, malignancies, chronic kidney disease (CKD), psychiatric illness, and inflammatory bowel disease (IBD). Many comorbidities and concomitant conditions must be considered when selecting the most appropriate therapy for a patient (Kaushik et al., 2019 and Monks et al., 2021) . Ongoing clinical trials and the development of new therapeutic targets contribute to the continuous improvement of available treatment options. Given the dynamic landscape of therapies, particularly when managing complex patients with multiple comorbidities, dermatologists are constantly challenged with the task of adeptly tailoring treatments to each psoriasis patient. This article systematically reviews the current evidence, presenting it as an updated Psoriasis Decision Tree to assist physicians in selecting tailored treatment options.
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Affiliation(s)
- Shivkar Amara
- The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anusha Pasumarthi
- The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Neil Parikh
- Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | | | - Mark Lebwohl
- The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - George Monks
- Department of Dermatology, University of Oklahoma College of Medicine in Oklahoma City, Oklahoma, USA
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3
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Daull P, Baudouin C, Liang H, Feraille L, Barabino S, Garrigue JS. Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases. Ocul Immunol Inflamm 2022; 30:1945-1955. [PMID: 34348575 DOI: 10.1080/09273948.2021.1957124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. PURPOSE This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. CONCLUSION these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis.
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Affiliation(s)
| | - Christophe Baudouin
- CHNO des Quinze-Vingts, IHU FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France.,Sorbonne Universités, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Hong Liang
- CHNO des Quinze-Vingts, IHU FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France.,Sorbonne Universités, INSERM, CNRS, Institut de la Vision, Paris, France
| | | | - Stefano Barabino
- Ocular Surface and Dry Eye Center, Ospedale L. Sacco, University of Milan, Milan, Italy
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4
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Warren DB, Haque S, McInerney MP, Corbett KM, Kastrati E, Ford L, Williams HD, Jannin V, Benameur H, Porter CJH, Chalmers DK, Pouton CW. Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations. Pharm Res 2021; 38:1531-1547. [PMID: 34561814 DOI: 10.1007/s11095-021-03099-5] [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: 07/08/2021] [Accepted: 08/21/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect. METHODS MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion. RESULTS These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model. CONCLUSIONS The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs.
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Affiliation(s)
- Dallas B Warren
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
| | - Shadabul Haque
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
| | | | - Karen M Corbett
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
| | - Endri Kastrati
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
| | - Leigh Ford
- Lonza Pharma, Biotech & Nutrition, Melbourne, Australia
| | | | | | | | | | - David K Chalmers
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
| | - Colin W Pouton
- Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
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5
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Nakase H. Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease. Gut Liver 2020; 14:7-19. [PMID: 30919602 PMCID: PMC6974326 DOI: 10.5009/gnl18203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/06/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022] Open
Abstract
The current goal of inflammatory bowel disease (IBD) treatment is a symptom-free everyday life accompanied by mucosal healing with minimal use of corticosteroids. Recent therapeutic advances, particularly, the emergence of anti-tumor necrosis factor (anti-TNF) antibodies, have changed the natural history of IBD. Additionally, these advances also led to the emergence of the therapeutic concept of the “treat to target” strategy. With the development of new drugs and clinical trials, not only biologics but also small molecules have been applied to clinical practice to better individualize and optimize therapy. However, if newer drugs, including anti-TNF therapies, are recommended for all patients diagnosed with IBD, a significant number of patients will be overtreated. The basic goal of IBD treatment is still to make the best use of conventional treatments based on IBD pathophysiology. Thus, physicians should be familiar with the modes of action of the available drugs. In this review, the author discusses the existing data for many approved drugs and provide insights for optimizing current treatments for the management of patients with IBD in the era of biologics.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Boctor A, Hugot JP, Leblanc T, Martinez-Vinson C, Allez M, Bellaïche M. Imatinib in Refractory Crohn Disease: A Series of 6 Cases. CROHN'S & COLITIS 360 2019. [DOI: 10.1093/crocol/otz034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Abstract
Biologics have revolutionized Crohn disease (CD) treatment. Nevertheless, absence or loss of response is frequent and alternative therapeutic options may be necessary. Imatinib is a tyrosine kinase inhibitor that is used in chronic myeloid leukemia. A positive impact on CD in 2 patients with chronic myeloid leukemia treated with imatinib led us to propose the drug in 4 additional patients with refractory CD. Four out of these 6 patients reached clinical and endoscopic remission at a median time of 3 months. Remission was maintained for 9 months to 7 years. Imatinib may thus be considered as new therapeutic options for refractory CD.
We report 6 CD patients treated with imatinib. Two of them because of a leukemia and 4 because of a disease refractory to all medical options. Four patients experienced full and sometimes prolonged remission of their digestive disease.
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Affiliation(s)
- Anna Boctor
- Service de Gastro-entérologie Pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jean-Pierre Hugot
- Service de Gastro-entérologie Pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
- Université de Paris et INSERM UMR1149, Paris, France
| | - Thierry Leblanc
- Service d’Hématologie Pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christine Martinez-Vinson
- Service de Gastro-entérologie Pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Matthieu Allez
- Université de Paris et INSERM U 940, Paris, France
- Service d’Hépato-gastro-entérologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Marc Bellaïche
- Service de Gastro-entérologie Pédiatrique, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
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Mathur R, Alam MM, Zhao XF, Liao Y, Shen J, Morgan S, Huang T, Lee H, Lee E, Huang Y, Zhu X. Induction of autophagy in Cx3cr1 + mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis. Mucosal Immunol 2019; 12:612-623. [PMID: 30765845 PMCID: PMC6927046 DOI: 10.1038/s41385-019-0146-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 01/21/2019] [Accepted: 01/27/2019] [Indexed: 02/04/2023]
Abstract
Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG-/- mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.
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Affiliation(s)
- Ramkumar Mathur
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA.
- The IBD Center, Division of Gastroenterology, Department of Medicine, Albany Medical College, Albany, NY, 12208, USA.
| | - Mahabub Maraj Alam
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Xiao-Feng Zhao
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Yuan Liao
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA
| | - Jeffrey Shen
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA
| | - Shannon Morgan
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Tingting Huang
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - HwaJeong Lee
- Department of Pathology, Albany Medical College, Albany, NY, 12208, USA
| | - Edward Lee
- Department of Surgery, Albany Medical College, Albany, NY, 12208, USA
| | - Yunfei Huang
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Xinjun Zhu
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA.
- The IBD Center, Division of Gastroenterology, Department of Medicine, Albany Medical College, Albany, NY, 12208, USA.
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Characterization of New Sustainable Acoustic Solutions in a Reduced Sized Transmission Chamber. BUILDINGS 2019. [DOI: 10.3390/buildings9030060] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In order to assess the airborne sound insulation of a new material or building solution, access to standardized laboratories, large and expensive facilities, and a sample area of at least 10 m2 are required. At the research and development stages of new sustainable acoustic materials for construction, it is not easy to make large sample areas available. Moreover, the financial investment in acoustic testing of materials during the research stage in standardized laboratories is excessive. In this work, the assessment of the airborne sound insulation of multi-layer partitions designed with new sustainable materials is presented. The assessed solutions are formed by green composite fiber boards as lightweight elements and a new material designed from sheep wool as absorbent material. The results of these 100% recyclable solutions are compared with lightweight element based solutions, which are commonly used for acoustic insulation. Characterization of those new sustainable solutions for building is leveraged in a reduced sized transmission chamber. The design, construction, and validation of this kind of laboratory are provided. This laboratory enables the assessment of the airborne sound insulation of a material in its research stage.
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Bhaskar N, Narasimhulu CA, Keewan E, Rohr M, Parthasarathy S. Proinflammatory Properties of Peroxidized Fat May Contribute to the Etiology of Crohn's Disease. J Med Food 2019; 22:162-169. [DOI: 10.1089/jmf.2018.0132] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Neha Bhaskar
- College of Medicine, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
- University of Miami, Coral Gables, Florida, USA
| | - Chandrakala Aluganti Narasimhulu
- College of Medicine, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
| | - Esraa Keewan
- College of Medicine, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
| | - Michael Rohr
- College of Medicine, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
| | - Sampath Parthasarathy
- College of Medicine, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
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10
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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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11
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Ma C, Hussein IM, Al-Abbar YJ, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, Siegel CA, Peyrin-Biroulet L, Pai RK, Vande Casteele N, D'Haens GR, Sandborn WJ, Feagan BG, Jairath V. Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review. Clin Gastroenterol Hepatol 2018; 16:1407-1419.e22. [PMID: 29596987 DOI: 10.1016/j.cgh.2018.02.051] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/21/2018] [Accepted: 02/27/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. METHODS We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. RESULTS Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts' Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. CONCLUSIONS In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
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Affiliation(s)
- Christopher Ma
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada; Robarts Clinical Trials, Western University, London, Ontario, Canada
| | | | | | - Remo Panaccione
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Claire E Parker
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Tran M Nguyen
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Reena Khanna
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Corey A Siegel
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Rish K Pai
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Niels Vande Casteele
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Geert R D'Haens
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands
| | - William J Sandborn
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Brian G Feagan
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
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12
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Reinglas J, Gonczi L, Kurt Z, Bessissow T, Lakatos PL. Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases. World J Gastroenterol 2018; 24:3567-3582. [PMID: 30166855 PMCID: PMC6113721 DOI: 10.3748/wjg.v24.i32.3567] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/09/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
The past decade has brought substantial advances in the management of inflammatory bowel diseases (IBD). The introduction of tumor necrosis factor (TNF) antagonists, evidence for the value of combination therapy, the recognition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The therapeutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn’s disease and in acute-severe ulcerative colitis. The safety and efficacy of these ‘older’ anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severity and response to therapy.
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Affiliation(s)
- Jason Reinglas
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
| | - Zsuzsanna Kurt
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
| | - Talat Bessissow
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
| | - Peter L Lakatos
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
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13
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Whitlock SM, Enos CW, Armstrong AW, Gottlieb A, Langley RG, Lebwohl M, Merola JF, Ryan C, Siegel MP, Weinberg JM, Wu JJ, Van Voorhees AS. Management of psoriasis in patients with inflammatory bowel disease: From the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2018; 78:383-394. [PMID: 29332708 DOI: 10.1016/j.jaad.2017.06.043] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 06/13/2017] [Accepted: 06/20/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND There is a significant association between psoriasis and inflammatory bowel disease (IBD). Many treatments for psoriasis and psoriatic arthritis are also used for IBD. OBJECTIVE To assess therapeutic options for patients with psoriasis and concurrent IBD. METHODS A systematic literature search was performed for clinical studies of biologic and systemic psoriasis medications in psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease, for the period from January 1, 1947, to February 14, 2017. Randomized, controlled, double-blinded studies were selected if available. If not, the next highest level of available evidence was selected. RESULTS Of the 2282 articles identified, 132 were selected. Infliximab and adalimumab have demonstrated efficacy in psoriasis, psoriatic arthritis, ulcerative; colitis, and Crohn's disease. Ustekinumab has demonstrated efficacy in psoriasis, psoriatic arthritis, and Crohn's disease. Certolizumab has demonstrated efficacy in psoriatic arthritis and Crohn's disease. Etanercept, secukinumab, brodalumab, and ixekizumab have demonstrated efficacy in psoriasis and psoriatic arthritis but may exacerbate or induce IBD. Guselkumab has demonstrated efficacy in psoriasis. LIMITATIONS There are no known clinical trials of treatment specifically for concurrent psoriasis and IBD. CONCLUSIONS Infliximab and adalimumab have demonstrated efficacy in psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease; other agents have demonstrated efficacy for some, but not all, of these indications.
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Affiliation(s)
- Scott M Whitlock
- Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia
| | - Clinton W Enos
- Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia
| | - April W Armstrong
- Department of Dermatology, University of Southern California, Los Angeles, California
| | - Alice Gottlieb
- Department of Medicine, New York Medical College, Valhalla, New York
| | - Richard G Langley
- Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mark Lebwohl
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Joseph F Merola
- Department of Dermatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
| | - Caitriona Ryan
- Division of Dermatology, Baylor University Medical Center, Dallas, Texas
| | | | - Jeffrey M Weinberg
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jashin J Wu
- Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
| | - Abby S Van Voorhees
- Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia.
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14
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Ma C, Dutton SJ, Cipriano LE, Singh S, Parker CE, Nguyen TM, Guizzetti L, Gregor JC, Chande N, Hindryckx P, Feagan BG, Jairath V. Systematic review with meta-analysis: prevalence, risk factors and costs of aminosalicylate use in Crohn's disease. Aliment Pharmacol Ther 2018; 48:114-126. [PMID: 29851091 DOI: 10.1111/apt.14821] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 04/13/2018] [Accepted: 05/02/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. AIMS To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. METHODS MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo-controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co-prescribed aminosalicylates in placebo arms was pooled using a random-effects model. Meta-regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. RESULTS Forty-two induction and 10 maintenance trials were included. The pooled proportion of patients co-prescribed aminosalicylates was 44% [95% CI: 39%-49%] in induction trials and 49% [95% CI: 35%-64%] in maintenance trials. There was substantial to considerable heterogeneity (I2 = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta-regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34-0.74] per 10-year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. CONCLUSIONS Over one-third of CD patients entering clinical trials are still co-prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy.
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Affiliation(s)
- C Ma
- Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Robarts Clinical Trials, Western University, London, ON, Canada
| | - S J Dutton
- Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - L E Cipriano
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Ivey Business School, Western University, London, ON, Canada
| | - S Singh
- Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA.,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - C E Parker
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - T M Nguyen
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - L Guizzetti
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - J C Gregor
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - N Chande
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - P Hindryckx
- Department of Gastroenterology, University Hospital of Ghent, Ghent, Belgium
| | - B G Feagan
- Robarts Clinical Trials, Western University, London, ON, Canada.,Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - V Jairath
- Robarts Clinical Trials, Western University, London, ON, Canada.,Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
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15
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Gionchetti P, Rizzello F, Annese V, Armuzzi A, Biancone L, Castiglione F, Comberlato M, Cottone M, Danese S, Daperno M, D'Incà R, Fries W, Kohn A, Orlando A, Papi C, Vecchi M, Ardizzone S. Use of corticosteroids and immunosuppressive drugs in inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease. Dig Liver Dis 2017; 49:604-617. [PMID: 28254463 DOI: 10.1016/j.dld.2017.01.161] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/15/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
The two main forms of intestinal bowel disease, namely ulcerative colitis and Crohn's disease, are not curable but can be controlled by various medical therapies. The Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) has prepared clinical practice guidelines to help physicians prescribe corticosteroids and immunosuppressive drugs for these patients. The guidelines consider therapies that induce remission in patients with active disease as well as treatment regimens that maintain remission. These guidelines complement already existing guidelines from IG-IBD on the use of biological drugs in patients with inflammatory bowel diseases.
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Affiliation(s)
- Paolo Gionchetti
- Department of Medical and Surgical Sciences, IBD Unit, University of Bologna, Bologna, Italy.
| | - Fernando Rizzello
- Department of Medical and Surgical Sciences, IBD Unit, University of Bologna, Bologna, Italy
| | - Vito Annese
- AOU Gastroenterology, Careggi University Hospital, Florence, Italy
| | - Alessandro Armuzzi
- IBD Unit Complesso Integrato Columbus-Gemelli Hospital Catholic University Foundation, Rome, Italy
| | - Livia Biancone
- University "Tor Vergata", Department of Systems Medicine, Rome, Italy
| | | | | | - Mario Cottone
- Department of Medicine, Pneumology and Nutrition Clinic, V. Cervello Hospital, Ospedali Riuniti Villa Sofia-Cervello University of Palermo, Palermo, Italy
| | - Silvio Danese
- IBD Center, Humanitas Clinical and Research Centre, Milan, Italy
| | - Marco Daperno
- Gastroenterology Unit, A.O. Ordine Mauriziano Hospital, Turin, Italy
| | - Renata D'Incà
- Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Walter Fries
- Clinical Unit for Chronic Bowel Disorders, Department of Internal Medicine, IBD Unit Messina, University of Messina, Messina, Italy
| | - Anna Kohn
- Department of Gastroenterology, San Camillo-Forlanini Hospital, Rome, Italy
| | - Ambrogio Orlando
- Department of Medicine, Pneumology and Nutrition Clinic, V. Cervello Hospital, Ospedali Riuniti Villa Sofia-Cervello University of Palermo, Palermo, Italy
| | - Claudio Papi
- Gastroenterology Unit, San Filippo Neri Hospital, Rome, Italy
| | - Maurizio Vecchi
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Donato Hospital, San Donato Milanese, Italy
| | - Sandro Ardizzone
- Gastroenterology and Digestive Endoscopy, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy
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16
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Jairath V, Zou G, Parker CE, MacDonald JK, Mosli MH, AlAmeel T, Al Beshir M, AlMadi M, Al-Taweel T, Atkinson NSS, Biswas S, Chapman TP, Dulai PS, Glaire MA, Hoekman D, Kherad O, Koutsoumpas A, Minas E, Restellini S, Samaan MA, Khanna R, Levesque BG, D'Haens G, Sandborn WJ, Feagan BG. Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease. Aliment Pharmacol Ther 2017; 45:1021-1042. [PMID: 28164348 DOI: 10.1111/apt.13973] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 07/08/2016] [Accepted: 01/16/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Minimising placebo response is essential for drug development. AIM To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.
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Affiliation(s)
| | | | | | | | - M H Mosli
- London, ON, Canada.,Jeddah, Saudi Arabia
| | | | | | | | | | | | | | | | - P S Dulai
- London, ON, Canada.,La Jolla, CA, USA
| | | | | | | | | | | | | | | | | | | | - G D'Haens
- London, ON, Canada.,Amsterdam, The Netherlands
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17
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Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment. Eur J Clin Pharmacol 2015; 71:773-99. [PMID: 26008212 DOI: 10.1007/s00228-015-1862-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/04/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. RESULTS It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics.
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18
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Abstract
Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.
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Affiliation(s)
- Robert V Bryant
- Translational Gastroenterology Unit, Oxford University Hospitals Trust , Oxford , UK
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19
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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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20
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Zenlea T, Peppercorn MA. Immunosuppressive therapies for inflammatory bowel disease. World J Gastroenterol 2014; 20:3146-3152. [PMID: 24696600 PMCID: PMC3964386 DOI: 10.3748/wjg.v20.i12.3146] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is comprised of Crohn’s disease and ulcerative colitis, both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course. For many years, the drug therapy was limited to sulfasalazine and related aminosalicylates, corticosteroids and antibiotics. Studies suggesting that the pathophysiology of these disorders relates to a disregulated, over-active immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD. This review details the mechanisms of action, clinical efficacy, and adverse effects of these agents.
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21
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22
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The effect of intravenous cyclosporine on rates of colonic surgery in hospitalized patients with severe Crohn's colitis. J Clin Gastroenterol 2012; 46:764-7. [PMID: 22751334 DOI: 10.1097/mcg.0b013e31824e14a8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The role of intravenous (IV) cyclosporine in severe Crohn's colitis (CC) is poorly studied. AIM Our primary aim was to determine the in-hospital colonic resection rate in patients with severe CC who received IV cyclosporine, and the potential predictors of resection among these patients. METHODS An inpatient pharmacy query of all patients who received IV cyclosporine at Mount Sinai Medical Center for 12.5 years after January 1, 1996 was reviewed. Patients with CC or indeterminate colitis favoring Crohn's were included and their medical records were reviewed. Subsequent need for colonic surgery was assessed. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of colonic surgery avoidance. Forward stepwise logistic regression was performed to determine independent predictors of surgery. RESULTS Forty-eight patients met our inclusion criteria. Prior thiopurine and anti-tumor necrosis factor (anti-TNF) use was 85% and 69%, respectively. The median follow-up time was 12 months (range, 1 to 60 mo). 12.5% of patients required colonic resection during their admission for IV cyclosporine. Anti-TNF use in the 4 weeks preceding IV cyclosporine was the only predictor of surgery in this setting (P=0.05). The cumulative colonic surgery avoidance rate was 72±13% at 6 months and 59±15% at 12 months. CONCLUSIONS The use of IV cyclosporine resulted in a low rate of in-hospitalization colonic surgery among CC patients with severe disease, the majority of whom previously failed anti-TNFs and thiopurines.
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23
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Cyclosporine: does it matter if it is given for Crohn's colitis or ulcerative colitis? J Clin Gastroenterol 2012; 46:721-2. [PMID: 22955259 DOI: 10.1097/mcg.0b013e31826aafd2] [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: 12/10/2022]
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24
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Ye BD, Yang SK, Shin SJ, Lee KM, Jang BI, Cheon JH, Choi CH, Kim YH, Lee H. [Guidelines for the management of Crohn's disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:141-79. [PMID: 22387837 DOI: 10.4166/kjg.2012.59.2.141] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) with uncertain etiopathogenesis. CD can involve any site of gastrointestinal tract from the mouth to anus and is associated with serious complications such as bowel strictures, perforations, and fistula formation. The incidence and prevalence rates of CD in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Although there are no definitive curative modalities for CD, various medical and surgical therapies are currently applied for diverse clinical situations of CD. However, a lot of decisions on the management of CD are made depending on the personal experiences and choices of physicians. To suggest preferable approaches to diverse problems of CD and to minimize the variations according to physicians, guidelines for the management of CD are needed. Therefore, IBD Study Group of the Korean Association for the Study of the Intestinal Diseases has set out to develop the guidelines for the management of CD in Korea. These guidelines were developed using the adaptation methods and encompass the treatment of inflammatory disease, stricturing disease, and penetrating disease. The guidelines also cover the indication of surgery, prevention of recurrence after surgery, and CD in pregnancy and lactation. These are the first Korean guidelines for the management of CD and the update with further scientific data and evidences is needed.
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Affiliation(s)
- Byong Duk Ye
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
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25
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26
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Oikonomou KA, Kapsoritakis AN, Stefanidis I, Potamianos SP. Drug-induced nephrotoxicity in inflammatory bowel disease. Nephron Clin Pract 2011; 119:c89-94; discussion c96. [PMID: 21677443 DOI: 10.1159/000326682] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine A seems well established, but recent data have suggested a possible role of biologic agents such as infliximab and adalimubab in renal impairment. The aim of this review is to summarize the nephrotoxic effects of medical treatment as well as to express possible caveats in the administration of novel agents in IBD.
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27
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Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106:630-42. [PMID: 21407186 DOI: 10.1038/ajg.2011.64] [Citation(s) in RCA: 190] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES There remains controversy regarding the efficacy of thiopurine analogs (azathioprine (AZA) and 6-mercaptopurine (6-MP)), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). We performed an updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in ulcerative colitis (UC) and Crohn's disease (CD). METHODS Only parallel group randomized controlled trials (RCTs) were considered eligible. Studies with adult IBD patients receiving immunosuppressive therapy compared with placebo for at least 14 days and up to 17 weeks for active disease, or at least 6 months in quiescent disease were analyzed. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat analysis. The data were summarized using relative risk (RR) and pooled using a random effects model. RESULTS Data on MTX and cyclosporine in IBD were limited although there were some data to support the use of intramuscular MTX in CD but not UC. There were five trials of AZA/6-MP in 380 active CD patients and there was no significant effect of therapy inducing remission (RR=0.87; 95% confidence interval (CI)=0.71-1.06). In quiescent CD, there were two trials involving 198 patients with no significant benefit of active therapy preventing relapse compared with placebo (RR=0.64; 95% CI=0.34-1.23). There were, however, three additional AZA withdrawal trials in 163 patients that indicated continuing medication did prevent relapse (RR=0.39; 95% CI=0.21-0.74). There were two AZA RCTs in 130 active UC patients that suggested a trend for benefit of therapy, but this did not reach statistical significance (RR=0.85; 95% CI=0.71-1.01). In quiescent UC, there were three trials involving 127 patients and there was a statistically significant benefit of AZA preventing relapse (RR=0.60; 95% CI=0.37-0.95). CONCLUSIONS Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for immunosuppressive therapy in IBD and more research is needed.
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Affiliation(s)
- Khurram J Khan
- Health Sciences Center, McMaster University, Hamilton, Ontario, Canada.
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28
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An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 2011; 106 Suppl 1:S2-25; quiz S26. [PMID: 21472012 DOI: 10.1038/ajg.2011.58] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Oikonomou K, Kapsoritakis A, Eleftheriadis T, Stefanidis I, Potamianos S. Renal manifestations and complications of inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:1034-45. [PMID: 20842645 DOI: 10.1002/ibd.21468] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Accepted: 07/29/2010] [Indexed: 12/11/2022]
Abstract
Renal manifestations and complications are not rare in patients with inflammatory bowel disease (IBD) and may present as nephrolithiasis, amyloidosis, tubulointerstitial nephritis, and glomerulonephritis. Symptoms of renal impairment are not always specific and since the underlying bowel disease is preponderant, renal function deterioration may be underestimated. Additionally, medical treatment of patients with IBD such as aminosalicylates, cyclosporine, and tumor necrosis factor-α inhibitors can cause renal complications, although direct correlation to bowel disease is not always clear. The well-documented renal manifestations and complications of IBD, as well as the possible renal side effects of new drugs, emphasize the need for periodic evaluation of renal function. New markers of renal function may facilitate early diagnosis and unravel the complex mechanisms responsible for kidney damage. The purpose of this review is to summarize the renal manifestations and complications as well as the markers of renal function utilized in IBD, attempting to shed more light on the pathophysiology of renal damage in IBD.
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Affiliation(s)
- Konstantinos Oikonomou
- Department of Gastroenterology, University of Thessaly, School of Medicine, Larissa, Greece.
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Zhang Y, Okamura S, Kudo T, Masuo T, Mori M. Calcineurin inhibition by polaprezinc in rats with experimentally-induced colitis. Life Sci 2011; 88:432-9. [PMID: 21219912 DOI: 10.1016/j.lfs.2010.12.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Revised: 12/01/2010] [Accepted: 12/11/2010] [Indexed: 12/19/2022]
Abstract
AIMS We investigated the therapeutic effect of polaprezinc (PZ), N-(3-aminopropionyl)-L-histidinato zinc, in rats with experimentally-induced colitis by focusing on calcineurin (CN) inhibition. CN plays a crucial role in T-cell activation and cytokine gene expression and is targeted by immunosuppressants such as cyclosporine and FK506. MAIN METHODS Colitis was induced into male Wistar rats by trinitrobenzene sulfonic acid and was treated with intrarectally administered PZ. The inflammation was assessed by the macroscopic damage score, colon wet weight, and proinflammatory mediator expression by RT-PCR analysis. Protein expression of calcineurin and the activation of its substrate, the nuclear factor of activated T cells (NFAT) transcription factor, were also studied. Calcineurin inhibition by PZ was investigated in in vitro experiments using colonic mucosa, purified calcineurin enzyme, and Jurkat T cells. KEY FINDINGS CN was activated in the colitic mucosa; PZ treatment inhibited CN activation, the expression of proinflammatory cytokines in the mucosa, and thereby ameliorated the experimental colitis in rats. In in vitro experiments, PZ inhibited CN activity, NFAT activation, interleukin-2 expression, and the growth of Jurkat T cells. In the effective concentrations, PZ did not affect cell viability. SIGNIFICANCE Our results suggest that PZ can be used as an immunosuppressive agent for the treatment of colitis through its inhibitory effect on CN activity.
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Affiliation(s)
- Yajing Zhang
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
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Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 2010; 116:6123-32. [PMID: 20837778 DOI: 10.1182/blood-2010-06-292391] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 μg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.
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Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D'Hoore A, Gassull M, Gomollón F, Hommes DW, Michetti P, O'Morain C, Oresland T, Windsor A, Stange EF, Travis SPL. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis 2010; 4:28-62. [PMID: 21122489 DOI: 10.1016/j.crohns.2009.12.002] [Citation(s) in RCA: 1020] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Accepted: 12/04/2009] [Indexed: 02/08/2023]
Affiliation(s)
- A Dignass
- Department of Medicine I, Markus-Krankenhaus, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany.
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Andreani SM, Dang HH, Grondona P, Khan AZ, Edwards DP. Rectovaginal fistula in Crohn's disease. Dis Colon Rectum 2007; 50:2215-22. [PMID: 17846837 DOI: 10.1007/s10350-007-9057-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2007] [Revised: 03/26/2007] [Accepted: 05/01/2007] [Indexed: 12/14/2022]
Abstract
PURPOSE Crohn's disease is characterized by transmural bowel inflammation and a tendency to form fistulas with adjacent structures. Several different fistulas have been described: enterocutaneous, enteroenteric, enterovesical, enterovaginal, and perineal. Rectovaginal fistulas are difficult to treat despite multimodal therapy. This study was designed to review the current strategic options to best manage this condition. METHODS We reviewed the English-language literature from 1966 to 2006, using PUBMED, targeting Crohn's disease involving vagina using key words "rectovaginal fistula and CD," "anovaginal fistula and CD," "anovaginal fistula," and "rectovaginal fistula." We excluded the involvement of the vagina from a pouch after a proctectomy. A total of 776 articles were found; 206 articles were identified and judged as being relevant on the basis of title-related articles and links were reviewed. Fifty-three articles were selected after reading the abstract or full manuscript. RESULTS The management of rectovaginal fistula, representing 9 percent of all fistulas, remains a challenge in the setting of Crohn's disease. Medical treatments are not favorable with low rates of long-term symptomatic control and unacceptable high rates of recurrence. Several novel and new surgical techniques have been described, and rectal advancement flap, in selected patients, seems to have the most successful results. CONCLUSIONS The management of rectovaginal fistula of Crohn's origin should involve both gastroenterologists and coloproctologists, with the best surgical results being achieved in patients receiving optimum medical therapy. More focused studies targeting these patients with the use of combined medical and surgical therapy are necessary.
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Affiliation(s)
- S M Andreani
- Department of Surgery, Frimley Park Hospital, Portsmouth Road, Frimley, Surrey, United Kingdom.
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Marlowe SNS, Leekassa R, Bizuneh E, Knuutilla J, Ale P, Bhattarai B, Sigdel H, Anderson A, Nicholls PG, Johnston A, Holt D, Lockwood DNJ. Response to ciclosporin treatment in Ethiopian and Nepali patients with severe leprosy Type 1 reactions. Trans R Soc Trop Med Hyg 2007; 101:1004-12. [PMID: 17669450 DOI: 10.1016/j.trstmh.2006.11.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2006] [Revised: 11/20/2006] [Accepted: 11/20/2006] [Indexed: 01/06/2023] Open
Abstract
Leprosy type 1 reactions (T1R) are immune-mediated events with inflammation of peripheral nerves and skin. We report the clinical outcomes of a closely monitored open prospective trial in which eight Nepali and 33 Ethiopian patients with T1Rs were treated with an Indian generic formulation of ciclosporin (Cn; 5-7.5 mg/kg/day) for 12 weeks and followed up for 24 weeks after starting treatment. Outcomes were measured using a clinical severity score. Among the Nepalis, 75-100% improved in all acute clinical parameters; 67-100% patients maintained improvement, except for those with acute sensory nerve impairment among whom 67% relapsed after stopping treatment. The skin lesions of all Ethiopians on 5 mg/kg/day of Cn improved and 50-60% had peripheral nerve function improvement. Most Ethiopians needed a higher dose of Cn to improve nerve impairment and neuritis, and 50-78% of them developed worse clinical severity scores when Cn was stopped. Four Ethiopians and two Nepalis developed elevated serum creatinine levels on 7.5 mg/kg/day Cn, and three (9%) Ethiopians developed treatable hypertension. This suggests that Cn monotherapy is an effective treatment for severe T1R with few adverse effects. A dose of 5 mg/kg/day seems efficacious in Nepalis, but a higher dose may be required in Ethiopian patients.
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Affiliation(s)
- S N S Marlowe
- London School of Hygiene and Tropical Medicine, Keppel Street, London, UK.
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Creed TJ, Probert CSJ. Review article: steroid resistance in inflammatory bowel disease - mechanisms and therapeutic strategies. Aliment Pharmacol Ther 2007; 25:111-22. [PMID: 17229236 DOI: 10.1111/j.1365-2036.2006.03156.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options. METHODS We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids. RESULTS Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies. CONCLUSIONS Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging.
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Affiliation(s)
- T J Creed
- University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol, UK.
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Abstract
Crohn's disease is a common indication for referral to pediatric gastroenterology. While most patients with Crohn's disease respond to standard induction therapy, steroid-refractory or steroid-dependent disease is a frequently encountered problem. This review discusses the data existing in both the adult and pediatric literature for medical therapy of refractory pediatric Crohn's disease.
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Affiliation(s)
- William A Faubion
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
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Braun F, Behrend M. Basic immunosuppressive drugs outside solid organ transplantation. Expert Opin Investig Drugs 2006; 15:267-91. [PMID: 16503764 DOI: 10.1517/13543784.15.3.267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immunosuppressive drugs are the backbone of solid organ transplantation. The introduction of new immunosuppressive drugs led to improved patient and organ survival rates. Nowadays, acute rejection can be reduced to a minimum. Individualization and avoidance of drug-related adverse effects became a new goal to achieve. The potency of immunosuppressive drugs makes them attractive for use in various autoimmune diseases; therefore, the experience on immunosuppressive drugs outside the field of organ transplantation is analysed in this review.
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Affiliation(s)
- Felix Braun
- General and Transplantation Surgery, University of Kiel, Germany
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Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130:940-87. [PMID: 16530532 DOI: 10.1053/j.gastro.2006.01.048] [Citation(s) in RCA: 334] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Gary R Lichtenstein
- Hospital of the University of Pennsylvania University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, USA
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Siegel CA, Sands BE. Review article: practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther 2005; 22:1-16. [PMID: 15963074 DOI: 10.1111/j.1365-2036.2005.02520.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Azathioprine, mercaptopurine, methotrexate, ciclosporin and tacrolimus all have their respective niches in the treatment of inflammatory bowel disease. These immunomodulators are potent and effective medications; however, they potentially have serious toxicity. To maximize benefit and minimize risk, clinicians must understand the mechanism of action, appropriate indications, range of toxicity and proper dosing of these medications. Furthermore, once initiating therapy, patients need to be monitored appropriately for evidence of efficacy and toxicity. This review includes the rationale behind recommendations for the management and monitoring of patients using immunomodulators. For the purine antagonists--azathioprine and mercaptopurine--the evidence for utility of thiopurine methyltransferase testing and mercaptopurine metabolite monitoring is addressed. The roles of liver biopsy and screening for methylenetetrahydrofolate reductase mutations in patients taking methotrexate are reviewed. With appropriate monitoring, the calcineurin inhibitors--ciclosporin and tacrolimus--can be used safely and effectively. Immunomodulators are important agents for the treatment of Crohn's disease and ulcerative colitis, and prescribing clinicians should be comfortable recognizing both their value and their limitations.
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Affiliation(s)
- C A Siegel
- Gastrointestinal Unit and MGH Crohn's and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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41
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Abstract
Infections have been reported in patients with inflammatory bowel disease (IBD), especially in association with anti-inflammatory and immunomodulatory medications used to treat IBD. Unfortunately, there is a dearth of information on infectious complication risk in patients with IBD. This review describes infectious complications reported in patients with IBD and provides a framework for future studies to assess potential risk factors and incidence for infection. Recommendations are also provided for prevention of infection.
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Affiliation(s)
- Faten N Aberra
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
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Abstract
Mesalamine has a well-established role in the management of ulcerative colitis. However, its role in the management of Crohn's disease (CD) is less clear. Studies evaluating its therapeutic value in CD have produced both positive and negative results. Meta-analyses have not clarified the situation, possibly because they have combined studies of different design. This debate critically examines the evidence for and against the use of mesalamine in CD.
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Affiliation(s)
- Michael A Kamm
- Department of Gastroenterology, St. Mark's Hospital, London, United Kingdom.
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McDonald JWD, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2005:CD000297. [PMID: 15846602 DOI: 10.1002/14651858.cd000297.pub2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease. OBJECTIVES To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine. SEARCH STRATEGY Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and July 2004. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials. SELECTION CRITERIA Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. AUTHORS' CONCLUSIONS Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.
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Affiliation(s)
- J W D McDonald
- Medicine, LHSC - UC, A-LL132, 339 Windermere Road, London, Ontario, Canada, N6A 5A5.
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Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N, Kletzel M, Whitington PF, Burt RK. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease. Gastroenterology 2005; 128:552-63. [PMID: 15765390 DOI: 10.1053/j.gastro.2004.11.051] [Citation(s) in RCA: 190] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.
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Affiliation(s)
- Yu Oyama
- Division of Immunotherapy, Department of Medicine, Northwestern University Medical Center, Chicago, Illinois 60611, USA.
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Abstract
The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.
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Affiliation(s)
- F N Aberra
- Department of Medicine, Center for Inflammatory Bowel Disease, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, 3400 Spruce Street, 3rd floor Ravdin Building, Philadelphia, PA 19104-4283, USA
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46
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Abstract
There is no medical or surgical treatment that provides a permanent cure for Crohn's disease (CD). However, an evolving understanding of the pathogenesis of CD has provided clinicians with a diversity of medical treatment options for the disease. The goal of therapy is to induce and maintain clinical remission. The efficacy of immune-modifying agents such as azathioprine/6-mercaptopurine and infliximab have supported a paradigm shift in CD treatment in which maintenance agents are introduced earlier in the disease course. At the same time, it is imperative to balance the efficacy, safety, and tolerability of medical therapy. Given the variable and relapsing clinical course of CD, the physician and patient should ideally develop an ongoing relationship that allows for individualization of treatment regimens, monitoring of response and side effects, and modification of the therapeutic strategy in the absence of improvement.
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Affiliation(s)
- Shamina Dhillon
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA.
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47
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Abstract
The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease had led us to believe that the old immunosuppressive drugs were destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of inflammatory bowel disease. Various factors may account for this change of view. Aim of the present review was to summarise key information currently available regarding the use of immunosuppressive drugs in the treatment of inflammatory bowel disease.
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Affiliation(s)
- R Caprilli
- GI Unit, Department of Clinical Science, University of Rome La Sapienza, Viale del Policlinico 155, 00161 Rome, Italy.
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Monguilhott Dalmarco E, Fröde TS, Medeiros YS. Additional evidence of acute anti-inflammatory effects of cyclosporin A in a murine model of pleurisy. Transpl Immunol 2004; 12:151-7. [PMID: 14967313 DOI: 10.1016/j.trim.2003.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2003] [Revised: 09/08/2003] [Accepted: 09/11/2003] [Indexed: 10/26/2022]
Abstract
INTRODUCTION It is well known that cyclosporin A (CsA) exhibits important anti-inflammatory effects, besides its immunosuppressive activity. However, the mechanisms by which CsA exerts these effects remain unclear. OBJECTIVE This study evaluated whether the acute administration of CsA significantly interfered in leukocyte migration, exudation, myeloperoxidase (MPO) and adenosine-deaminase activities and nitrate/nitrite levels, in a mouse model of pleurisy. MATERIALS AND METHODS Pleurisy was induced by carrageenan (1%) treatment and the parameters were analyzed 4 and 48 h after. Groups of animals were previously treated with different doses of CsA and compared with non-treated groups. RESULTS CsA (0.1-5 mg/kg, intraperitoneal, 1 h before pleurisy induction) inhibited neutrophil migration (P<0.05), but not the exudation that occurred 4 h after pleurisy induction. At this time, CsA (1 mg/kg, 1 h before) also decreased nitrate/nitrite levels and MPO activity (P<0.01). CsA (2 mg/kg, 0.5 h before) was also effective in decreasing mononuclear influx, exudation and nitrate/nitrite levels 48 h after onset of inflammation. CONCLUSIONS These results indicate that the acute administration of CsA is able to reduce the two leukocyte populations that occur both at 4 and 48 h after pleurisy induction, late exudation (48 h), MPO activity (4 h) and nitrate/nitrite levels (4 and 48 h). Taken together, these findings indicate that CsA has acute anti-inflammatory effects in immunocompetent animals.
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Affiliation(s)
- Eduardo Monguilhott Dalmarco
- Department of Clinical Analysis, Center of Health Sciences, Universidade Federal de Santa Catarina, Campus Universitário - Trindade, 88040-970 Florianopolis, SC, Brazil
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49
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Abreu MT. Choosing Therapy on the Basis of Disease Classifications in Inflammatory Bowel Disease. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2004; 7:169-179. [PMID: 15149579 DOI: 10.1007/s11938-004-0038-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Crohn's disease and ulcerative colitis (UC) are heterogeneous disorders, and as such, the response to therapy is likewise heterogeneous. Therefore, stratification of patients into distinct phenotypes and potentially genotypes will lead to more definitive answers with respect to evaluation of novel and established therapies.
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Affiliation(s)
- Maria T. Abreu
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 110 George Burns Road, Davis Building, Room 4005, Los Angeles, CA 90048, USA.
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50
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Loftus CG, Egan LJ, Sandborn WJ. Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease. Gastroenterol Clin North Am 2004; 33:141-69, vii. [PMID: 15177532 DOI: 10.1016/j.gtc.2004.02.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
In the past decade, immunosuppressive drugs have come to play an integral role in the treatment of patients with inflammatory bowel disease. Cyclosporine, microemulsion cyclosporine, tacrolimus, and mycophenolate mofetil can be considered for the treatment of patients with refractory inflammatory Crohn's disease, fistulizing Crohn's disease, and severe ulcerative colitis. This article reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in patients with inflammatory bowel disease, with emphasis on pharmacology, results in controlled clinical trials, and safety, and issues related to dosing and toxicity monitoring.
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Affiliation(s)
- Conor G Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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