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Fukuchi T, Kawashima K, Koga H, Utsunomiya R, Sugiyama K, Shimazu K, Eguchi T, Ishihara S. Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse. J Clin Biochem Nutr 2022; 70:197-204. [PMID: 35400813 PMCID: PMC8921725 DOI: 10.3164/jcbn.21-112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.
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Affiliation(s)
- Takumi Fukuchi
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Kousaku Kawashima
- Department of Internal Medicine II, Shimane University Faculty of Medicine
| | - Hideaki Koga
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Ran Utsunomiya
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Kohei Sugiyama
- Department of Gastroenterology and Hepatology, Iseikai Hospital
| | - Keiji Shimazu
- Department of Nephrology, Saiseikai Nakatsu Hospital
| | - Takaaki Eguchi
- Department of Gastroenterology and Hepatology, Saiseikai Nakatsu Hospital
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University Faculty of Medicine
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Kyriakos N, Papaefthymiou A, Giakoumis M, Iatropoulos G, Mantzaris G, Liatsos C. Informed consent in inflammatory bowel disease: a necessity in real-world clinical practice. Ann Gastroenterol 2021; 34:466-475. [PMID: 34276184 PMCID: PMC8276362 DOI: 10.20524/aog.2021.0635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 03/08/2021] [Indexed: 11/11/2022] Open
Abstract
In modern medicine, any medical intervention has to be supported by a patient's informed consent. Challenges to this process include the specificity and complexity of medical information being provided, the patient's ability to comprehend the information, the medical uncertainty of the outcomes, and the physician's legal concerns. Important elements of the consent process are respect for the patient's autonomy and self-determination, appropriate disclosure and verification of their understanding, and voluntariness. In inflammatory bowel disease (IBD), pharmaceutical treatment carries significant risks, making discussion and illustration of the treatment critical for decision making. This review aims to emphasize the importance of the informed consent process in routine IBD clinical practice, and suggests an appropriate way of informing patients about the medical treatment on offer. The information that has to be comprehensively presented before consent includes: i) treatment goal; ii) basic characteristics of treatment (route and timetable of drug administration, drug efficacy, adverse events); and iii) consequences of staying untreated. The IBD physician's main concerns must include ensuring not only that the information being provided is detailed and objective, but also that the decision-making process is shared with the patient. Ultimately, the process of obtaining informed consent in real-world clinical practice is undoubtedly of great importance, for both upholding the principles of medical ethics and avoiding legal conflicts.
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Affiliation(s)
- Nikolaos Kyriakos
- Gastroenterology Department, 401 General Army Hospital of Athens, Greece (Nikolaos Kyriakos, Apostolis Papaefthymiou, Marios Giakoumis, Christos Liatsos)
| | - Apostolis Papaefthymiou
- Gastroenterology Department, 401 General Army Hospital of Athens, Greece (Nikolaos Kyriakos, Apostolis Papaefthymiou, Marios Giakoumis, Christos Liatsos)
| | - Marios Giakoumis
- Gastroenterology Department, 401 General Army Hospital of Athens, Greece (Nikolaos Kyriakos, Apostolis Papaefthymiou, Marios Giakoumis, Christos Liatsos)
| | - George Iatropoulos
- Medical Oncology Department, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Australia (George Iatropoulos)
| | - Gerasimos Mantzaris
- Gastroenterology Department, General Hospital of Athens “Evangelismos-Ophtalmiatreion Athinon-Polykliniki”, Athens, Greece (Gerasimos Mantzaris)
| | - Christos Liatsos
- Gastroenterology Department, 401 General Army Hospital of Athens, Greece (Nikolaos Kyriakos, Apostolis Papaefthymiou, Marios Giakoumis, Christos Liatsos)
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Xing S, Jiao Y, Salehzadeh M, Soma KK, Huan T. SteroidXtract: Deep Learning-Based Pattern Recognition Enables Comprehensive and Rapid Extraction of Steroid-Like Metabolic Features for Automated Biology-Driven Metabolomics. Anal Chem 2021; 93:5735-5743. [PMID: 33784068 DOI: 10.1021/acs.analchem.0c04834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Despite the vast amount of metabolic information that can be captured in untargeted metabolomics, many biological applications are looking for a biology-driven metabolomics platform that targets a set of metabolites that are relevant to the given biological question. Steroids are a class of important molecules that play critical roles in many physiological systems and diseases. Besides known steroids, there are a large number of unknown steroids that have not been reported in the literature. The ability to rapidly detect and quantify both known and unknown steroid molecules in a biological sample can greatly accelerate a broad range of steroid-focused life science research. This work describes the development and application of SteroidXtract, a convolutional neural network (CNN)-based bioinformatics tool that can recognize steroid molecules in mass spectrometry (MS)-based untargeted metabolomics using their unique tandem MS (MS2) spectral patterns. SteroidXtract was trained using a comprehensive set of standard MS2 spectra from MassBank of North America (MoNA) and an in-house steroid library. Data augmentation strategies, including intensity thresholding and Gaussian noise addition, were created and applied to minimize data overfitting caused by the limited number of standard steroid MS2 spectra. The CNN model embedded in SteroidXtract was further compared with random forest and XGBoost using nested cross-validations to demonstrate its performance. Finally, SteroidXtract was applied in several metabolomics studies to demonstrate its sensitivity, specificity, and robustness. Compared to conventional statistics-driven metabolomics data interpretation, our work offers a novel automated biology-driven approach to interpreting untargeted metabolomics data, prioritizing biologically important molecules with high throughput and sensitivity.
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Affiliation(s)
- Shipei Xing
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
| | - Yibo Jiao
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
| | - Melody Salehzadeh
- Department of Zoology, Faculty of Science, University of British Columbia, Vancouver Campus, 6270 University Boulevard, Vancouver, BC V6T 1Z4, Canada
| | - Kiran K Soma
- Department of Zoology, Faculty of Science, University of British Columbia, Vancouver Campus, 6270 University Boulevard, Vancouver, BC V6T 1Z4, Canada.,Department of Psychology, Faculty of Arts, University of British Columbia, Vancouver Campus, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada
| | - Tao Huan
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
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Chen XL, Mao JW, Wang YD. Selective granulocyte and monocyte apheresis in inflammatory bowel disease: Its past, present and future. World J Gastrointest Pathophysiol 2020; 11:43-56. [PMID: 32435521 PMCID: PMC7226913 DOI: 10.4291/wjgp.v11.i3.43] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/05/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, are not fully understood so far. Therefore, IBD still remains incurable despite the fact that significant progress has been achieved in recent years in its treatment with innovative medicine. About 20 years ago, selective granulocyte and monocyte apheresis (GMA) was invented in Japan and later approved by the Japanese health authority for IBD treatment. From then on this technique was extensively used for IBD patients in Japan and later in Europe. Clinical trials from Japan and European countries have verified the effectiveness and safety of GMA therapy in patients with IBD. In 2013, GMA therapy was approved by China State Food and Drug Administration for therapeutic use for the Chinese IBD patients. However, GMA therapy has not been extensively used in China, although a few clinical studies also showed that it was effective in clinical and endoscopic induction of remission in Chinese IBD patients with a high safety profile. This article reviews past history, present clinical application as well as the future prospective of GMA therapy for patients with IBD.
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Affiliation(s)
- Xiu-Li Chen
- Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Jing-Wei Mao
- Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Ying-De Wang
- Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
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Derijks LJJ, Wong DR, Hommes DW, van Bodegraven AA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease. Clin Pharmacokinet 2019; 57:1075-1106. [PMID: 29512050 DOI: 10.1007/s40262-018-0639-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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Affiliation(s)
- Luc J J Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, PO Box 7777, 5500 MB, Veldhoven, The Netherlands.
| | - Dennis R Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Daniel W Hommes
- Center for Inflammatory Bowel Diseases, UCLA, Los Angeles, CA, USA
| | - Adriaan A van Bodegraven
- Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
- Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
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Fukuchi T, Koga H, Kaichi S, Ishikawa A, Horita T, Araki R, Yokota A, Namba Y, Kyo M, Eguchi T, Shimazu K. Single-Needle Intensive Granulocyte and Monocyte Adsorptive Apheresis Is Suitable for Elderly Patients With Active Ulcerative Colitis Taking no Corticosteroids or Biologics. Ther Apher Dial 2019; 23:224-232. [PMID: 31025824 DOI: 10.1111/1744-9987.12819] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 01/25/2019] [Indexed: 12/29/2022]
Abstract
Twice-weekly intensive granulocyte/monocyte adsorptive apheresis is effective and safe for ulcerative colitis, but maintaining two blood access routes is problematic. We previously reported that intensive granulocyte/monocyte adsorptive apheresis using a single needle in ulcerative colitis is effective and safe. We hypothesized that the efficacy and safety of single-needle intensive granulocyte/monocyte adsorptive apheresis for ulcerative colitis would especially benefit the elderly. We enrolled 17 elderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis, 27 elderly ulcerative colitis patients to receive double-needle intensive granulocyte/monocyte adsorptive apheresis, and 52 nonelderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis. Remission and mucosal healing rates after treatment did not differ significantly between elderly ulcerative colitis patients receiving single-needle apheresis and the other two groups. In addition, no serious adverse effects, including blood clots, were observed in single-needle intensive granulocyte/monocyte adsorptive apheresis patients. Single-needle intensive granulocyte/monocyte adsorptive apheresis might be a novel alternative therapeutic option for elderly ulcerative colitis patients before considering corticosteroids.
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Affiliation(s)
- Takumi Fukuchi
- Department of Gastroenterology and Hepatology, Iseikai Hospital, Osaka, Japan
| | - Hideaki Koga
- Department of Gastroenterology and Hepatology, Iseikai Hospital, Osaka, Japan
| | - Shinji Kaichi
- Department of Gastroenterology and Hepatology, Iseikai Hospital, Osaka, Japan
| | - Akira Ishikawa
- Department of Gastroenterological Surgery, Iseikai Hospital, Osaka, Japan
| | - Takahisa Horita
- Dialysis Center, Iseikai Fuzoku Iseikai Clinic, Osaka, Japan
| | - Ryota Araki
- Dialysis Center, Juso Iseikai Clinic, Osaka, Japan
| | - Atsushi Yokota
- Dialysis Center, Shin-Osaka Iseikai Clinic, Osaka, Japan
| | | | - Masahiro Kyo
- Dialysis Center, Osaka Umeda Iseikai Dialysis Clinic, Osaka, Japan
| | - Takaaki Eguchi
- Department of Gastroenterology and Hepatology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Keiji Shimazu
- Department of Nephrology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
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Saniabadi AR, Tanaka T, Yamamoto T, Kruis W, Sacco R. Granulomonocytapheresis as a cell-dependent treatment option for patients with inflammatory bowel disease: Concepts and clinical features for better therapeutic outcomes. J Clin Apher 2018; 34:51-60. [PMID: 30407662 DOI: 10.1002/jca.21670] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 05/25/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are major phenotypes of the chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms. The chronic nature of IBD means that patients require life-long medications, and this may lead to drug dependency, loss of response together with adverse side effects as additional morbidity factors. The efficacy of antitumour necrosis factor (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation and perpetuation of IBD. However, cytokines are released by myeloid lineage leucocytes like the CD14+ CD16+ monocyte phenotype. Additionally in IBD, myeloid leucocytes are elevated with activation behavior, while lymphocytes are compromised. Therefore, patients' leucocytes appear logical targets of therapy. Adsorptive granulomonocytapheresis (GMA) with an Adacolumn uses carriers, which interact with the Fcγ receptor expressing leucocytes and deplete the elevated myeloid leucocytes, while the neutrophils, which re-enter the circulation via the Adacolumn outflow (≥40%) are phagocytosed by CD19 B-cells to become interleukin (IL)-10 producing Bregs or CD19high CD1Dhigh B-cells. IL-10 is an anti-inflammatory cytokine. GMA has been applied to treat patients with IBD. The efficacy outcomes have been impressive as well as disappointing, the clinical response to GMA defines the patients' disease course and severity at entry. Efficacy outcomes in patients with deep ulcers together with extensive loss of the mucosal tissue are not encouraging, while patients without these features respond well and attain a favorable long-term disease course. Accordingly, for responder patients, GMA fulfills a desire to be treated without drugs.
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Affiliation(s)
| | - Tomotaka Tanaka
- Department of Gastroenterology, Akitsu Prefectural Hospital, Hiroshima, Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Hazu Medical Centre, Yokkaichi, Japan
| | - Wolfgang Kruis
- Evangelisches Krankenhaus Kalk, Cologen University, Cologne, Germany
| | - Rodolfo Sacco
- Department of Gastroenterology, Pisa University Hospital, Pisa, Italy
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Shimazu K, Fukuchi T, Kim I, Noguchi Y, Iwata M, Koyama S, Ubukata S, Tanaka A. Efficacy and Usefulness of New Single-Needle Intensive Granulocyte and Monocyte Adsorptive Apheresis in Active Ulcerative Colitis Patients Without Corticosteroids and Biologics. Ther Apher Dial 2017; 20:383-9. [PMID: 27523079 DOI: 10.1111/1744-9987.12470] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Indexed: 12/23/2022]
Abstract
Intensive granulocyte and monocyte adsorptive apheresis (GMA) twice weekly is effective and safe for patients with active ulcerative colitis (UC), but the requirement for maintaining two blood access routes is problematic. Here we compared the efficacy and safety of one-route blood access intensive GMA using a single-needle (SN) and conventional two-route blood access intensive GMA using a double-needle (DN) in patients with active UC not undergoing corticosteroid therapy. Among 80 active UC patients, 38 patients received SN intensive GMA and 42 patients received DN intensive GMA. The clinical remission ratio and mucosal healing ratio at 6 weeks, and the cumulative non-relapse ratio at 52 weeks did not differ significantly between groups. In addition, no serious or mild adverse effects were observed in SN intensive GMA. SN intensive GMA may be an adequate and novel therapeutic option for active UC as an alternative therapy before using corticosteroids.
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Affiliation(s)
- Keiji Shimazu
- Department of Nephrology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Takumi Fukuchi
- Department of Gastroenterology and Hepatology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Insung Kim
- Clinical Engineering, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Yuki Noguchi
- Clinical Engineering, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Megumi Iwata
- Department of Nephrology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Shintaro Koyama
- Department of Gastroenterology and Hepatology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan.,Department of Gastroenterology and Hepatology, Kobe Hokuto Hospital, Kobe, Japan
| | - Satoshi Ubukata
- Department of Gastroenterology and Hepatology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Atsuo Tanaka
- Department of Nephrology, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
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Hashiguchi K, Takeshima F, Akazawa Y, Matsushima K, Minami H, Machida H, Yamaguchi N, Shiozawa K, Ohba K, Ohnita K, Ichikawa T, Isomoto H, Nakao K. Advantages of fecal lactoferrin measurement during granulocyte and monocyte adsorptive apheresis therapy in ulcerative colitis. Digestion 2015; 91:208-17. [PMID: 25823500 DOI: 10.1159/000375301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 01/16/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Fecal lactoferrin has been introduced as a useful tool for the diagnosis and monitoring of inflammatory bowel disease (IBD). The aim of this study was to assess if fecal lactoferrin can be employed to predict or estimate the effect of granulocyte and monocyte adsorptive apheresis (GMA) in ulcerative colitis (UC). METHODS This was a prospective study involving 21 patients with UC. Patients with moderately-to-severely active UC who were scheduled to undergo GMA were recruited. Changes in fecal lactoferrin concentration were compared between the GMA-responder and -nonresponder groups. RESULTS In the GMA-responder group, fecal lactoferrin significantly increased 1 week after the introduction of GMA and then significantly decreased after GMA sessions. Fecal lactoferrin concentrations were significantly higher in the GMA-responder group than in the GMA-nonresponder group at 1 and 2 weeks after the introduction of GMA. Multivariate logistic regression analysis revealed that fecal lactoferrin concentration 1 week after the introduction of GMA was the most contributing factor for the effectiveness of GMA in patients with UC. CONCLUSIONS In the GMA-responder group, fecal lactoferrin concentration significantly increased 1 week after the introduction of GMA. Fecal lactoferrin may be beneficial for predicting clinical response of GMA in patients with UC at an early stage of GMA treatment.
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Affiliation(s)
- Keiichi Hashiguchi
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan
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C. JAIMELUBASCHER. ERRORES FRECUENTES EN EL DIAGNÓSTICO Y TRATAMIENTO DE LOS PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL. REVISTA MÉDICA CLÍNICA LAS CONDES 2015. [DOI: 10.1016/j.rmclc.2015.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Sacco R, Tanaka T, Yamamoto T, Bresci G, Saniabadi AR. Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders. Expert Rev Gastroenterol Hepatol 2015; 9:327-33. [PMID: 25160857 DOI: 10.1586/17474124.2014.953060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Cytokines such as TNF-α have a validated role in the immunopathogensis of ulcerative colitis (UC), and intercepting inflammatory cytokines is currently the best option for maximizing treatment efficacy. One of the major sources of inflammatory cytokines are myeloid linage leucocytes (granulocytes, monocytes), which are present in great numbers in the colonic tissue. Their selective depletion by adsorptive granulocyte, monocyte apheresis (GMA), should be therapeutic in patients with UC, although until now efficacy outcomes have been both encouraging and disappointing. The authors' view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.
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Affiliation(s)
- Rodolfo Sacco
- Department of Gastroenterology-Pisa University Hospital, Pisa, Italy
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12
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Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel disease by adsorptive leucocytapheresis: A desire to treat without drugs. World J Gastroenterol 2014; 20:9699-9715. [PMID: 25110409 PMCID: PMC4123360 DOI: 10.3748/wjg.v20.i29.9699] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.
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Tanaka T, Sugiyama S, Goishi H, Kajihara T, Akagi M, Miura T. Treatment of children and adolescents with ulcerative colitis by adsorptive depletion of myeloid lineage leucocytes as monotherapy or in combination with low dose prednisolone after failure of first-line medications. BMC Gastroenterol 2013; 13:130. [PMID: 23961883 PMCID: PMC3765231 DOI: 10.1186/1471-230x-13-130] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 08/10/2013] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Currently available drugs for the treatment of ulcerative colitis (UC) include salicylates, thiopurines, corticosteroids and new anti-tumour necrosis factor (TNF)-α biologics. Among these medications, corticosteroids in children and adolescents may adversely affect the patients' growth and development. Further, UC patients have elevated and activated myeloid lineage leucocytes including the CD14 + CD16+ monocytes, which release TNF-α as a significant exacerbating factor. Accordingly, depletion of these cells by granulocyte/monocyte adsorption (GMA) should alleviate inflammation and promote UC remission. The objective of this study was to evaluate the efficacy of GMA in children and adolescents in whom conventional first-line medications had failed to induce remission. METHODS In a single centre setting, between 2007 and 2012, a total of 24 consecutive children and adolescents, age 11-19 years were given mesalazine or sulphasalazine as a first-line medication. Seventeen patients relapsed or did not respond to the first-line medications, and received GMA with the Adacolumn, 2 sessions in the first week, and then weekly, up to 11 sessions. Patients who achieved a decrease of ≥5 in the clinical activity index (CAI) were to continue with GMA, while non-responders were to receive 0.5 to 1.0 mg/kg/day prednisolone (PSL) plus additional GMA sessions similar to GMA responder cases. At entry and week 12, patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control. RESULTS Seven patients achieved remission with the first-line medications and did not receive GMA. Five patients did not respond to the first 5 GMA sessions and received PSL plus GMA, while 12 patients responded to the first 5 GMA sessions and received additional sessions. At entry, the average CAI was 12.7 ± 2.5, range 8-17, and the average endoscopic index was 8.5 ± 1.5, range 7-11. The corresponding values at week 12 were 2.1 ± 0.2, range 1-4 (P < 0.001) and 2.4 ± 0.2, range 1-4 (P < 0.001). PSL was tapered to 0 mg within 3 months. CONCLUSIONS With the strategy we applied in this study, all 24 consecutive patients achieved remission. In growing patients with active UC refractory to first-line medications, GMA was associated with clinical remission and mucosal healing, while in non-responders to GMA monotherapy, addition of a low dose PSL enhanced the efficacy of GMA and tapering of the PSL dose soon after remission was not associated with UC relapse. Therefore, the majority of young corticosteroid naive UC patients in whom first-line salicylates have failed may respond to GMA and be spared from additional drug therapy. Avoiding corticosteroids at an early stage of UC should ensure better long-term clinical course.
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Affiliation(s)
- Tomotaka Tanaka
- Department of Gastroenterology, Akitsu Prefectural Hospital, 4388 Akitsu cho, Hiroshima 739-2402, Japan.
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Tanaka T, Sugiyama S, Goishi H, Kajihara T, Akagi M, Miura T. Treatment of children and adolescents with ulcerative colitis by adsorptive depletion of myeloid lineage leucocytes as monotherapy or in combination with low dose prednisolone after failure of first-line medications. BMC Gastroenterol 2013. [PMID: 23961883 DOI: 10.1016/s1873-9946(13)60351-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Currently available drugs for the treatment of ulcerative colitis (UC) include salicylates, thiopurines, corticosteroids and new anti-tumour necrosis factor (TNF)-α biologics. Among these medications, corticosteroids in children and adolescents may adversely affect the patients' growth and development. Further, UC patients have elevated and activated myeloid lineage leucocytes including the CD14 + CD16+ monocytes, which release TNF-α as a significant exacerbating factor. Accordingly, depletion of these cells by granulocyte/monocyte adsorption (GMA) should alleviate inflammation and promote UC remission. The objective of this study was to evaluate the efficacy of GMA in children and adolescents in whom conventional first-line medications had failed to induce remission. METHODS In a single centre setting, between 2007 and 2012, a total of 24 consecutive children and adolescents, age 11-19 years were given mesalazine or sulphasalazine as a first-line medication. Seventeen patients relapsed or did not respond to the first-line medications, and received GMA with the Adacolumn, 2 sessions in the first week, and then weekly, up to 11 sessions. Patients who achieved a decrease of ≥5 in the clinical activity index (CAI) were to continue with GMA, while non-responders were to receive 0.5 to 1.0 mg/kg/day prednisolone (PSL) plus additional GMA sessions similar to GMA responder cases. At entry and week 12, patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control. RESULTS Seven patients achieved remission with the first-line medications and did not receive GMA. Five patients did not respond to the first 5 GMA sessions and received PSL plus GMA, while 12 patients responded to the first 5 GMA sessions and received additional sessions. At entry, the average CAI was 12.7 ± 2.5, range 8-17, and the average endoscopic index was 8.5 ± 1.5, range 7-11. The corresponding values at week 12 were 2.1 ± 0.2, range 1-4 (P < 0.001) and 2.4 ± 0.2, range 1-4 (P < 0.001). PSL was tapered to 0 mg within 3 months. CONCLUSIONS With the strategy we applied in this study, all 24 consecutive patients achieved remission. In growing patients with active UC refractory to first-line medications, GMA was associated with clinical remission and mucosal healing, while in non-responders to GMA monotherapy, addition of a low dose PSL enhanced the efficacy of GMA and tapering of the PSL dose soon after remission was not associated with UC relapse. Therefore, the majority of young corticosteroid naive UC patients in whom first-line salicylates have failed may respond to GMA and be spared from additional drug therapy. Avoiding corticosteroids at an early stage of UC should ensure better long-term clinical course.
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Affiliation(s)
- Tomotaka Tanaka
- Department of Gastroenterology, Akitsu Prefectural Hospital, 4388 Akitsu cho, Hiroshima 739-2402, Japan.
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Tominaga K, Nakano M, Hoshino M, Kanke K, Hiraishi H. Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone. BMC Gastroenterol 2013; 13:41. [PMID: 23452668 PMCID: PMC3599731 DOI: 10.1186/1471-230x-13-41] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Accepted: 02/25/2013] [Indexed: 02/06/2023] Open
Abstract
Background Patients with ulcerative colitis (UC) are treated with prednisolone (PSL), which causes adverse side effects. Extracorporeal granulocyte/monocyte adsorption (GMA) with an Adacolumn depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines. We were interested to evaluate the efficacy, safety and the treatment cost for PSL and GMA. Methods Forty-one patients with active UC had achieved remission with GMA, at 1 or 2 sessions/week, up to 10 sessions (n=24) or with orally administered PSL (1mg/kg bodyweight, n=17). Clinical activity index (CAI) ≤4 was considered clinical remission. Following remission, patients received 5-aminosalicylic acid (2250-3000mg/day) or sulphasalazine (4000-6000mg/day) as maintenance therapy and were followed for 600 days. The total treatment cost was assessed based on 1€=150JPY. Results PSL was tapered after two weeks, and discontinued when a patient achieved remission. The average time to the disappearance of at least one major UC symptom (haematochezia, diarrhoea, or abdominal discomfort) was 15.3 days in the GMA group and 12.7 days in the PSL group, while time to remission was 27.9 days in the GMA group and 27.6 days in the PSL group, CAI 0.8 and 2.0, respectively. The Kaplan-Meier plots showed similar remission maintenance rates over the 600 days follow-up period. The average medical cost was 12739.4€/patient in the GMA group and 8751.3€ in the PSL group (P<0.05). In the GMA group, 5 transient adverse events were observed vs 10 steroid related adverse events in the PSL group (P<0.001). Conclusions In appropriately selected patients, GMA has significant efficacy with no safety concern. The higher cost of GMA vs PSL should be compromised by good safety profile of this non-pharmacological treatment intervention.
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Affiliation(s)
- Keiichi Tominaga
- Department of Gastroenterology, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
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Nakano R, Iwakiri R, Ikeda Y, Kishi T, Tsuruoka N, Shimoda R, Sakata Y, Yamaguchi K, Fujimoto K. Factors affecting short- and long-term effects of leukocyte removal therapy in active ulcerative colitis. J Gastroenterol Hepatol 2013; 28:303-8. [PMID: 23339387 DOI: 10.1111/jgh.12049] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2012] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIM Leukocyte removal therapy (LRT) is recognized as an effective treatment for active ulcerative colitis (UC). In this study, factors associated with the efficacy and long-term effects of LRT were evaluated. METHODS From April 1998 to March 2010, 98 patients with moderate to severe UC were randomly assigned to granulocyte and monocyte/macrophage adsorptive apheresis (GMA) (n = 47) or leukocytapheresis (LCAP) (n = 51) treatment. Patients received two sessions of LRT in the first week, followed by three weekly administrations. All patients were treated with 5-aminosalicylic acid and corticosteroid. Steroid doses were tapered if patients achieved clinical improvement. Clinical remission was defined as a decrease in clinical activity index to < 4 and endoscopic findings to Matts' grade 1 or 2. When clinical activity index decreased but still remained ≥ 5 and Matts' grading was 1 or 2, the patient was considered to have improved. Patients were observed for at least 1 year and diagnosed as relapsed when additional treatment was required. RESULTS Seventy-one (73%) patients achieved clinical remission or improvement. No significant difference was found between LCAP and GMA. Increased age, ≥ 3 attacks of UC, and ≥ 2 sessions of LRT were indicative of refractoriness to LRT. During 1 year observation, 28 patients were relapsed. Duration of UC, ≥ 3 attacks of UC, and ≥ 2 sessions of LRT were indicative of refractoriness to the long-term effects of LRT. CONCLUSION Both GMA and LCAP were effective to treat active UC. However, long duration of UC, multiple UC attacks, and past history of LRT reduce the efficacy.
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Affiliation(s)
- Ryo Nakano
- Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan
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Fukunaga K, Yokoyama Y, Kamokozuru K, Nagase K, Nakamura S, Miwa H, Matsumoto T. Adsorptive granulocyte/monocyte apheresis for the maintenance of remission in patients with ulcerative colitis: a prospective randomized, double blind, sham-controlled clinical trial. Gut Liver 2012; 6:427-33. [PMID: 23170145 PMCID: PMC3493721 DOI: 10.5009/gnl.2012.6.4.427] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 01/20/2012] [Accepted: 02/01/2012] [Indexed: 12/19/2022] Open
Abstract
Background/Aims Weekly granulocyte/monocyte adsorption (GMA) to deplete elevated and activated leucocytes should serve as a non-pharmacological intervention to induce remission in patients with ulcerative colitis (UC). This trial assessed the efficacy of monthly GMA as a maintenance therapy to suppress UC relapse. Methods Thirty-three corticosteroid refractory patients with active UC received 10 weekly GMA sessions as a remission induction therapy. They were then randomized to receive one GMA session every 4 weeks (True, n=11), extracorporeal circulation without the GMA column every 4 weeks (Sham, n=11), or no additional intervention (Control, n=11). The primary endpoint was the rate of avoiding relapse (AR) over 48 weeks. Results At week 48, the AR rates in the True, Sham, and Control groups were 40.0%, 9.1%, and 18.2%, respectively. All patients were steroid-free, but no statistically significant difference was seen among the three arms. However, in patients who could taper their prednisolone dose to <20 mg/day during the remission induction therapy, the AR in the True group was better than in the Sham (p<0.03) or Control (p<0.05) groups. Conclusions Monthly GMA may potentially prevent UC relapse in patients who have achieved remission through weekly GMA, especially in patients on <20 mg/day PSL at the start of the maintenance therapy.
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Affiliation(s)
- Ken Fukunaga
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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Processed blood volume impacts clinical efficacy in patients with ulcerative colitis undergoing adsorptive depletion of myeloid lineage leucocytes. J Gastroenterol 2012; 47:49-55. [PMID: 21915624 DOI: 10.1007/s00535-011-0464-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 08/03/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hitherto, therapeutic depletion of granulocytes and monocytes by adsorption (GMA) has been associated with significant and insignificant efficacy in patients with ulcerative colitis (UC). Further, the processed blood volume in one GMA session has been fixed at 30 mL/min × 60 min, regardless of patients' body weight (BW). We were interested to see the efficacy and safety of GMA when administered in relation to patients' BW. METHODS Sixty patients were randomly assigned to the routine GMA (n = 30) and to GMA adjusted to patients' BW, 60 mL/kg (n = 30). GMA was done with the Adacolumn, up to 10 sessions over 10 weeks. At entry and 1 week post last GMA, patients were clinically and endoscopically evaluated. Remission was defined as clinical activity index (CAI) ≤4, whereas mucosal remission was defined as endoscopic index (EI) ≤3. RESULTS In the BW group, the processed volume/session was 3,260 ± 581 versus 1,800 mL in the routine group (P < 0.001). In the BW group, 25 of 30 patients (83.3%) achieved remission versus 19 of 30 patients (63.3%) in the routine group. The average CAI in the BW group fell from 9.6 ± 2.6 to 2.3 ± 2.1 versus from 9.1 ± 2.4 to 4.0 ± 2.1 (P < 0.05) in the routine group. Similarly, the EI in the BW group fell from 9.4 ± 1.3 to 2.1 ± 2.1 versus from 9.2 ± 1.8 to 4.5 ± 2.3 (P < 0.01). CONCLUSIONS GMA adjusted to patients' BW and at a vastly greater processed volume produces significantly higher efficacy as compared with the routine GMA protocol. Further, in this study, up to twofold higher processed volume caused no safety concern.
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Yokoyama Y, Fukunaga K, Ikeuchi H, Kamikozuru K, Hida N, Ohda Y, Iimuro M, Yoshida K, Kikuyama R, Kato K, Nagase K, Nakamura S, Miwa H, Matsumoto T. The CD4+CD28null and the regulatory CD4+CD25High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy. Cytokine 2011; 56:466-70. [PMID: 21802311 DOI: 10.1016/j.cyto.2011.06.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 06/27/2011] [Indexed: 11/26/2022]
Abstract
The CD4+CD25High T-cell phenotype has an essential immunoregulatory role, while the CD4+CD28null T-cell reflects immune pathology. We investigated the profiles of the CD4+CD25High and the CD4+CD28null T-cell phenotypes in patients with ulcerative colitis (UC) during active and quiescent phases as well as following colectomy. Fifty-nine UC patients, 34 active (UCa) and 25 quiescent (UCq) together with 19 healthy controls (HC) were included. Ten of 34 UCa patients underwent colectomy due to unremitting UC (UCo). Immunohistochemical phenotypic of the peripheral blood lymphocytes bearing CD4, CD25 or CD28 was done for analyzes by a multiparameter fluorescence activated cell sorting technique. The expression of the CD4+CD25High phenotype was higher in UCq (P<0.01) or UCo (P<0.01) group vs UCa group. Further, the expression of the CD4+CD28null phenotype in UCa or UCo group was higher than in the HC group (P<0.05). However, the expression of the CD4+CD28null phenotype up to 12 months after colectomy was not significantly different from the levels in the same patients during acute phase. Our impression is that a high CD4+CD25High T-cell reflects alleviation of inflammation, while the expression of the CD4+CD28null T-cell phenotype is an etiologic feature in UC patients, and is maintained after removing the affected colon.
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Affiliation(s)
- Yoko Yokoyama
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
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Setoyama H, Ido A, Numata M, Moriuchi A, Yamaji N, Tamai T, Funakawa K, Fujita H, Sakiyama T, Uto H, Oketani M, Tsubouchi H. Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis. Life Sci 2011; 89:269-75. [PMID: 21763320 DOI: 10.1016/j.lfs.2011.06.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2010] [Revised: 06/04/2011] [Accepted: 06/08/2011] [Indexed: 01/27/2023]
Abstract
AIMS Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration. We previously reported that systemic administration of recombinant human HGF (rh-HGF) ameliorated experimental colitis. However, an increase in serum HGF concentrations may induce undesired systemic effects, limiting the use of rh-HGF. To avoid possible side effects, we investigated the safety and efficacy of rectally administered rh-HGF as a treatment for experimental colitis. MAIN METHODS We measured serum human HGF concentration following a single rectal enema of rh-HGF. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis were treated with rectal enemas of rh-HGF once a day for seven days. The degree of mucosal injuries and the proliferative activity of the colon epithelium were examined. KEY FINDINGS Rats administered a rectal enema of rh-HGF at a dose of 0.1 mg/ml or less had no detectable rh-HGF in the serum. Repeated enemas of rh-HGF at this dose significantly reduced mucosal injuries, both with respect to lesion size and inflammatory cell infiltration. This regimen also stimulated proliferation of epithelial cells surrounding injured mucosa; however, the cell proliferation of uninjured mucosa was not affected by this local treatment. SIGNIFICANCE Rectally administered rh-HGF selectively accelerates the repair of injured mucosa in rat experimental colitis without systemic exposure to HGF. Rectal enemas of HGF are thus a potential novel and safe therapy for IBD.
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Affiliation(s)
- Hitoshi Setoyama
- HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan
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Abstract
BACKGROUND Medical treatment for inflammatory bowel disease (IBD) has advanced significantly over the past decade, but it is important to communicate effectively the balance of benefits and risks of therapy to patients to facilitate informed medical decisions. AIM To review the available data describing the risk of side effects of IBD medications and to describe effective methods for communicating risk. METHODS To identify relevant articles for this review, a PubMed search was conducted using relevant key words and phrases. In addition, reference lists from identified manuscripts were searched and recent abstracts from National meetings were reviewed. RESULTS The steroid-sparing medications used for the treatment of IBD all carry risks of both common and rare adverse events. Trade-offs need to be made between the risks of these medications vs. the risks of poorly treated disease and corticosteroids. There has been significant research on how best to present risk data to patients, which is summarized in this review. CONCLUSIONS To ensure that our patients understand their choices and feel comfortable with their treatment, we need to communicate risk data to patients clearly. Patients comprehend absolute numbers better than relative risk, and when available, pictorial representations of data are preferred over solely presenting numerical outcomes.
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Affiliation(s)
- C A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
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Lindberg A, Eberhardson M, Karlsson M, Karlén P. Long-term follow-up with Granulocyte and Monocyte Apheresis re-treatment in patients with chronically active inflammatory bowel disease. BMC Gastroenterol 2010; 10:73. [PMID: 20604939 PMCID: PMC2914086 DOI: 10.1186/1471-230x-10-73] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 07/06/2010] [Indexed: 12/12/2022] Open
Abstract
Background Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn®) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity. Methods Fifteen patients with ulcerative colitis and 25 patients with Crohn's disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months. Results Clinical response was seen in 85% and complete remission in 65% of the patients. Ten patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months. Fourteen patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of seven patients were successfully re-treated for the third time, all of three patients for the fourth time and one for a fifth time. Conclusions IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.
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Affiliation(s)
- Annelie Lindberg
- Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset SE-118 83 Stockholm, Sweden
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Cassina M, Fabris L, Okolicsanyi L, Gervasi MT, Memmo A, Tiboni GM, Di Gianantonio E, Clementi M. Therapy of inflammatory bowel diseases in pregnancy and lactation. Expert Opin Drug Saf 2009; 8:695-707. [DOI: 10.1517/14740330903357463] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Abstract
Ulcerative colitis is a chronic inflammatory disease that affects the colon and rectum. Its pathogenesis is probably multifactorial including the influx of certain cytokines into the colonic mucosa, causing disease activity and relapse. The hypothesis of removing such cytokines from the circulation by leukocytapheresis was implemented to reduce disease activity, maintain remission, and prevent relapse. Many recent reports not only in Japan, but also in the West, have highlighted its beneficial effects in both adult and pediatric patients. Large placebo-controlled studies are needed to confirm the available data in this regard. In this article, we shed some light on the use of leukocyte apheresis in the management of autoimmune diseases, especially ulcerative colitis.
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Affiliation(s)
- Ahmed Helmy
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
| | - Maheeba Abdulla
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Ingvar Kagevi
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Khalid Al Kahtani
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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Fukunaga K, Nagase K, Kusaka T, Hida N, Ohda Y, Yoshida K, Tozawa K, Kamikozuru K, Iimuro M, Nakamura S, Miwa H, Matsumoto T. Cytapheresis in patients with severe ulcerative colitis after failure of intravenous corticosteroid: a long-term retrospective cohort study. Gut Liver 2009; 3:41-7. [PMID: 20479900 DOI: 10.5009/gnl.2009.3.1.41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2008] [Accepted: 11/01/2008] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND/AIMS Cytapheresis (CAP) is a novel strategy for ulcerative colitis (UC). However, there is insufficient data on the long-term outcome of UC patients who achieve remission by CAP. This study involved patients with severe UC who refracted to intravenous (iv) corticosteroid. METHODS Forty-seven UC patients who had received CAP therapy for the first time within 1 year after UC diagnosis were followed for 36 months. One of the inclusion criteria was a clinical activity index (CAI) of >/=7 points at the end of a 2-week iv course of corticosteroid therapy. CAP therapy consisted of ten sessions over 10 weeks. RESULTS CAP induced clinical remission (CAI</=4) in 70.2% patients (33/47). The number of submissions for colectomy was higher for severe UC at entry (CAI>/=12, n=25) than for moderately severe UC at entry (7</=CAI<12, p=15; p<0.02). The cumulative rates of avoiding surgery and relapse were 54.5% and 24.2%, respectively, at 36 months in patients who responded to CAP therapy. This was similar to that of iv cyclosporine reported recently. CONCLUSIONS This study suggest that CAP is an effective therapy in patients who are refractory to conventional medications including iv corticosteroid. Increased remission rates should be expected in refractory patients with moderately severe UC.
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Affiliation(s)
- Ken Fukunaga
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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Abstract
(Table is included in full-text article.)The development of biologicals such as infliximab to intercept TNF-alpha validates the current perception that certain cytokines are major factors in the immunopathogenesis of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Furthermore, major sources of inflammatory cytokines include activated peripheral granulocytes and monocytes (GM), which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated GM should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated GM by extracorporeal adsorption (GMA). Published data show that GMA in patients with steroid-dependent or steroid-refractory IBD is associated with striking efficacy and tapering or discontinuation of steroids, whereas in steroid-naïve patients GMA spared patients from steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse significantly suppressed relapse, thus sparing the patients from the morbidity associated with active IBD. First ulcerative colitis episode, steroid naivety and short disease duration seem to be good predictors of response to GMA and on the basis of our experience, GMA seems to have an excellent safety profile.
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Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Kageoka M, Ikeya K, Yamada M, Kikuyama M, Iwaoka Y, Hirayama K, Nagata S, Sato Y, Hosoda Y. Intensive granulocyte and monocyte adsorption versus intravenous prednisolone in patients with severe ulcerative colitis: an unblinded randomised multi-centre controlled study. Dig Liver Dis 2008; 40:433-40. [PMID: 18296130 DOI: 10.1016/j.dld.2008.01.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Revised: 12/06/2007] [Accepted: 01/07/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Several uncontrolled studies have reported on the efficacy of adsorptive depletion of peripheral blood granulocytes and monocytes/macrophages (GM) in patients with moderate or severe ulcerative colitis. This study was to compare the efficacy and safety of intensive GMA with intensive intravenous prednisolone in patients with severe ulcerative colitis. METHODS Seventy patients with clinical activity index 10-23 were randomly assigned to intensive GMA with the Adacolumn, at 2 sessions/week in the first 3 weeks and then 1 session/week for up to 11 sessions (n = 35) or intravenous prednisolone, 40-60 mg/day for 5-10 days (n = 35). No patient received immunomodulators within 8 weeks prior to entry. Clinical response based on intention to treat was assessed at weeks 2, 6 and 12. RESULTS Four patients in the prednisolone group and two patients in the GMA group discontinued in week 1. At weeks 2, 6 and 12, the remission (clinical activity index < or = 4) rates (%) in the GMA group were 17.1, 54.4, 74.3, respectively. The corresponding values in the prednisolone group were 25.7, 51.4 and 48.6. Further, at week 12, 27 patients (77%) in the GMA group and 5 patients (14%) in the prednisolone group were steroid free (P = 0.0076). In the GMA group, flushing and light-headedness were observed in 5 patients versus typical steroid side effects in 29 patients of the prednisolone group. CONCLUSIONS In this clinical response to GMA was comparable or better than prednisolone. Further, the response to GMA was slower than to intravenous prednisolone, but was more sustainable than the latter.
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Affiliation(s)
- H Hanai
- Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 430-0846, Japan.
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Bianchi Porro G, Cassinotti A, Ferrara E, Maconi G, Ardizzone S. Review article: the management of steroid dependency in ulcerative colitis. Aliment Pharmacol Ther 2007; 26:779-94. [PMID: 17767462 DOI: 10.1111/j.1365-2036.2007.03334.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Approximately 20% of patients with ulcerative colitis have a chronic active disease often requiring several courses of systemic steroids in order to achieve remission, but followed by relapse of symptoms during steroid tapering or soon after their discontinuation. Although short term control of symptoms can be achieved with steroid treatment, this pattern of drug response, known as steroid-dependency, leads to important complications of the treatment, while a significant proportion of patients requires colectomy. AIM To review the studies currently available specifically evaluating the management of steroid-dependent ulcerative colitis. RESULTS The clinical and biological mechanisms of steroid-dependency are not well understood compared with those determining steroid-refractoriness. Very few evidence-based data are available concerning the management of patients with steroid-dependent ulcerative colitis. The therapeutic role of aminosalicylates, thiopurines, methotrexate, infliximab, leukocyte apheresis and other drugs in the treatment of steroid-dependent ulcerative colitis are evaluated. CONCLUSIONS Outcomes of studies in steroid-refractory patients may not be applicable to steroid-dependency. Trials are needed to define the correct approaches and new strategies to ameliorate the therapy of steroid-dependent ulcerative colitis.
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Affiliation(s)
- G Bianchi Porro
- Department of Clinical Science, Chair of Gastroenterology, L Sacco University Hospital, Milan, Italy.
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29
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Bhatia JK, Korelitz BI, Panagopoulos G, Lobel E, Mirsky F, Sultan K, DiSanti W, Chun A, Keenan G, Mamun K. A prospective open-label trial of Remicade in patients with severe exacerbation of Crohn's disease requiring hospitalization: a comparison with outcomes previously observed in patients receiving intravenous hydrocortisone. J Clin Gastroenterol 2007; 41:677-81. [PMID: 17667052 DOI: 10.1097/mcg.0b013e31802c2a23] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE To evaluate treatment response to intravenous (IV) infliximab (IFX) as a first-line therapy in patients hospitalized for severe Crohn's disease and compare it with our earlier data using IV hydrocortisone. METHODS Seventeen cases received IFX (5 mg/kg) and were matched for the same goal of therapy to those who had received hydrocortisone (300 mg/d). The Crohn's and Colitis Foundation of America-International Organization of Inflammatory Bowel Disease (CCFA-IOIBD) score was obtained for the IFX-treated cases on admission and daily and the Crohn's disease activity index (CDAI) score weekly throughout the hospitalization and compared with those who received hydrocortisone. Discharge was guided by the same criteria in both groups. RESULTS For the IFX group, the admission mean CCFA-IOIBD score was 13.5 (+/-4.4). Eight of 17 patients achieved a clinical response with a mean score of 4 (+/-1.5), representing a >or=50% reduction from baseline to discharge. The mean admission score for the hydrocortisone group was 17.75 (+/-7.1) with 13 of 16 achieving a mean score of 4.5 (+/-2.3). The mean discharge score for the 17 IFX patients was 6.9 (+/-3) and for the hydrocortisone group was 5.9 (+/-3.2). Median length of hospitalization for the IFX patients was 4 days (range 1 to 9) and 7.5 (5 to 15) days for the hydrocortisone group (P<0.001). CONCLUSIONS IFX therapy was an effective first-line agent in patients with severe Crohn's disease who require hospitalization and therefore a primary treatment option. Most patients receiving IFX can anticipate a briefer hospitalization than with IV hydrocortisone. Failure of an early response can provide an opportunity to consider an alternate form of therapy sooner with IFX than with hydrocortisone.
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Affiliation(s)
- Jyoti K Bhatia
- Department of Gastroenterology, Lenox Hill Hospital, and New York University School of Medicine, New York, NY 10021, USA
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Abstract
Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel disease (IBD). Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor (TNF)-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages (GM) are major sources. Further, in IBD, peripheral GMs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GM by receptor-mediated adsorption (GMA). Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid naïve patients (the best responders), GMA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GMA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.
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Affiliation(s)
- Hiroyuki Hanai
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 4300846, Japan
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31
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WATANABE K, OSHITANI N, KAMATA N, INAGAWA M, YAMAGAMI H, HIGUCHI K, ARAKAWA T. Efficacy and endoscopic prediction of cytapheresis therapy in patients with refractory and steroid-dependent ulcerative colitis. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1746-6342.2006.00038.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Gionchetti P, Rizzello F, Lammers KM, Morselli C, Sollazzi L, Davies S, Tambasco R, Calabrese C, Campieri M. Antibiotics and probiotics in treatment of inflammatory bowel disease. World J Gastroenterol 2006; 12:3306-13. [PMID: 16733845 PMCID: PMC4087861 DOI: 10.3748/wjg.v12.i21.3306] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Many experimental and clinical observations suggest that intestinal microflora plays a potential role in the pathogenesis of inflammatory bowel disease (IBD). Manipulation of the luminal content using antibiotics or probiotics represents a potentially effective therapeutic option. The available studies do not support the use of antibiotics in ulcerative colitis (UC). Antibiotics are effective in treating septic complications of Crohn’s disease (CD) but their use as a primary therapy is more controversial, although this approach is frequently and successfully adopted in clinical practice.
There is evidence that probiotic therapy may be effective in the prevention and treatment of mild to moderate UC. In contrast, a lack of successful study data at present precludes the widespread use of probiotics in the treatment of CD.
Both antibiotics and probiotics appear to play a beneficial role in the treatment and prevention of pouchitis and further trials are warranted to fully quantify their clinical efficacy.
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Affiliation(s)
- Paolo Gionchetti
- Department of Internal Medicine and Gastroenterology, Bologna, Italy.
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33
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Kanai T, Hibi T, Watanabe M. The logics of leukocytapheresis as a natural biological therapy for inflammatory bowel disease. Expert Opin Biol Ther 2006; 6:453-66. [PMID: 16610976 DOI: 10.1517/14712598.6.5.453] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are debilitating idiopathic inflammatory bowel diseases (IBDs) with symptoms that impair ability to function and quality of life. The aetiology of IBD is inadequately understood and, therefore, drug therapy has been empirical instead of based on sound understanding of the disease mechanisms. This has been a major factor for poor drug efficacy and treatment-related side effects that often add to disease complications. The development of biologicals, notably infliximab, to block TNF-alpha reflects some progress, but there is major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD by its very nature is exacerbated and perpetuated by inflammatory cytokines, including TNF-alpha, IL-6 and IL-12, for which activated peripheral blood lymphocytes, monocytes/macrophages and granulocytes are major sources. Hence, activated leukocytes should be appropriate targets of therapy. At present, three strategies are available for removing excess and activated leukocytes by leukocytapheresis: centrifugation, Adacolumn and Cellsorba. Centrifugation can deplete lymphocytes or total leukocytes, whereas Adacolumn selectively adsorbs granulocytes and monocytes together with a smaller fraction of lymphocytes (FcgammaR- and complement receptor-bearing leukocytes), and Cellsorba non-selectively removes all three major leukocyte populations. Efficacy has ranged from 'none' to an impressive 93% together with excellent safety profiles and downmodulation of inflammation factors. Furthermore, leukocytapheresis has shown strong drug-sparing effects and reduced the number of patients requiring colectomy or exposure to unsafe immunosuppressants, such as cyclosporin A. Leukocytapheresis removes from the body cells that contribute to IBD and, therefore, unlike drugs, it is not expected to induce dependency or refractoriness.
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Affiliation(s)
- Takanori Kanai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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34
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Saniabadi AR, Hanai H, Suzuki Y, Ohmori T, Sawada K, Yoshimura N, Saito Y, Takeda Y, Umemura K, Kondo K, Ikeda Y, Fukunaga K, Nakashima M, Beretta A, Bjarnason I, Lofberg R. Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? J Clin Apher 2005; 20:171-84. [PMID: 15892107 DOI: 10.1002/jca.20046] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory and/or autoimmune diseases like ulcerative colitis (UC) or Crohn's disease (CD) are debilitating chronic disorders that poorly respond to pharmacological interventions. Further, drug therapy has adverse effects that add to disease complications. The current thinking is that disorders like inflammatory bowel disease (IBD) reflect an over exuberant immune activation driven by cytokines including TNF-alpha. Major sources of cytokines include myeloid leukocytes (granulocytes, monocytes/macrophages), which in IBD are elevated with activation behavior and are found in vast numbers within the inflamed intestinal mucosa. Accordingly, myeloid cells should be the targets of therapy. Adacolumn is filled with cellulose acetate beads that selectively adsorb and deplete myeloid cells and a small fraction of lymphocytes (FcgammaR and complement receptors bearing cells). In one study, 20 steroid naive patients with moderate (n = 14) or severe (n = 6) UC according to Rachmilewitz despite 1.5-2.25 g/day of 5-aminosalicylic acid received 6 to 10 Adacolumn sessions at 2 sessions/week. Efficacy was assessed 1 week after the last session. The majority of patients responded to 6 sessions, 17 (85%) achieved remission. In 2 of the 3 non-responders, CAI was 8 and 12 in 1; all 3 had deep colonic ulcers at study initiation. Decreases were seen in total leukocytes (P = 0.003), % neutrophils (P = 0.003), % monocytes (P = 0.004), an increase in lymphocytes (P = 0.001), decreases in C-reactive protein (P = 0.0002), and rises in blood levels of soluble TNF-alpha receptors I (P = 0.0007), II (P = 0.0045). In a separate study, a case with very severe steroid refractory UC who received up to 11 sessions responded well and avoided colectomy. Further, myeloid cell purging with Adacolumn has been associated with the release of IL-1 receptor antagonist, suppression of TNF-alpha, IL-1beta, IL-6, IL-8, down-modulation of L-selectin and the chemokine receptor CXCR3. In conclusion, selective depletion of myeloid cells appears to induce anti-inflammatory effects and represents a non-pharmacological treatment for patients with active IBD. The treatment has a clear drug-sparing role. Changes in blood levels of inflammatory and anti-inflammatory factors are thought to contribute to the efficacy of this procedure.
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Affiliation(s)
- Abbi R Saniabadi
- Japan Immunoresearch Laboratories, Nishiyokote Machi, Takasaki, Japan.
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Makiyama K, Takeshima F, Hamamoto T. Efficacy of rebamipide enemas in active distal ulcerative colitis and proctitis: a prospective study report. Dig Dis Sci 2005; 50:2323-9. [PMID: 16416182 DOI: 10.1007/s10620-005-3055-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Accepted: 03/22/2005] [Indexed: 02/06/2023]
Abstract
Rebamipide has a broad spectrum of pharmacological actions that include suppression of neutrophil functions and stimulation of mucosal epithelial cell regeneration by increasing the expression of epithelial growth factor (EGF) and the EGF receptor. Sixteen patients with active ulcerative colitis (UC; mild in 1 patient, moderate in 11, and severe in 4) were recruited. Enemas containing 150 mg rebamipide per dosing were administered during the daytime after passage of stool, twice a day for 4 weeks. UC disease activity index (UC-DAI), endoscopic activity index (EAI), and Floren's grading (FG) of mucosal biopsy specimens were measured at entry and at 4 weeks. Five of 16 patients did not complete the study, and therefore, final efficacy assessment was done on 11 patients who completed the 4 weeks of treatment. Improvements were observed in UC-DAI (P = 0.0049), EAI (P = 0.0043), and FG (P = 0.0084). There was no serious rebamipide-related side effect in any of the 16 patients. In conclusion, rebamipide topical therapy appears to be effective for the treatment of mildly to moderately active distal UC. Further controlled studies are warranted for this promising drug.
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Affiliation(s)
- K Makiyama
- Department of Endoscopy, Nagasaki University Hospital of Medicine and Dentistry, Sakamoto, Nagasaki, Japan.
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36
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Domènech E, Hinojosa J, Esteve-Comas M, Gomollón F, Herrera JM, Bastida G, Obrador A, Ruiz R, Saro C, Gassull MA. Granulocyteaphaeresis in steroid-dependent inflammatory bowel disease: a prospective, open, pilot study. Aliment Pharmacol Ther 2004; 20:1347-52. [PMID: 15606397 DOI: 10.1111/j.1365-2036.2004.02288.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Uncontrolled studies suggest that granulocyteaphaeresis might be useful in the management of active ulcerative colitis. AIM To assess the efficacy of granulocyteaphaeresis treatment in active steroid-dependent inflammatory bowel disease. METHODS We conducted a multicentre, prospective, open, pilot study in patients with steroid-dependent inflammatory bowel disease. All patients were started on 60 mg/day of prednisone; after 1 week, a five-session programme of granulocyteaphaeresis (once per week) was started. The steroid dose was tapered weekly if there was clinical improvement. Remission was defined as an inactive clinical activity index together with complete withdrawal of steroids at week 6. The patients were followed up for at least 6 months or until disease relapse. RESULTS Twenty-six patients (14 ulcerative colitis, 12 Crohn's disease) were included. More than a half had been previously treated with immunomodulators. Remission was achieved in 62 and 70% of ulcerative colitis and Crohn's disease, respectively. During a median follow-up of 12.6 months, six of eight ulcerative colitis patients maintained their clinical remission; however, only one Crohn's disease patient remained in remission after the first 6 months of follow-up. CONCLUSIONS Granulocyteaphaeresis is a safe treatment option in inflammatory bowel disease. A five-session programme of granulocyteaphaeresis seems to be efficient in the treatment of steroid-dependent ulcerative colitis, but not in Crohn's disease.
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Affiliation(s)
- E Domènech
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
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37
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Lichtenstein GR, Hanauer SB, Kane SV, Present DH. Crohn's is not a 6-week disease: lifelong management of mild to moderate Crohn's disease. Inflamm Bowel Dis 2004; 10 Suppl 2:S2-10. [PMID: 15475770 DOI: 10.1097/00054725-200407002-00002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Crohn's disease is an idiopathic, chronic inflammatory disorder of the digestive tract with heterogeneous clinical presentations. Crohn's is currently not a curable disease, and patients are faced with a lifetime of recurrent disease flare-ups and remissions. Management strategies for Crohn's must therefore be targeted toward lifelong management, taking into consideration not only the short-term but also the long-term aspects of the disease. With this in mind, here we review the classifications and natural history of Crohn's disease and discuss possible predictive factors for the disease evolution in a patient. Here we also evaluate the current preferable treatment practices, based on scientifically valid research and collective clinical experience, for the management of mild to moderate Crohn's disease.
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38
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Abstract
Current evidence strongly suggests that Crohn's disease is caused by an abnormal response to enteric flora. This review examines the current evidence for medical management of Crohn's disease, particularly focusing on alternative therapies to corticosteroids in managing disease relapses and preventing long-term complications.
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Affiliation(s)
- Adrian Thuraisingam
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals, Liverpool L7 8XP
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39
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Affiliation(s)
- David B Sachar
- Mount Sinai School of Medicine, New York, New York 10029, USA.
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40
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Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Croitoru K, Seidman E, Leddin DJ, Bitton A, Drouin E, Cohen A, Greenberg GR. Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled trial. Gastroenterology 2002; 123:33-40. [PMID: 12105831 DOI: 10.1053/gast.2002.34225] [Citation(s) in RCA: 131] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Although antibiotics are frequently used to treat Crohn's disease, this practice is not supported by strong evidence from randomized trials. METHODS We conducted a double-blind multicenter study of patients with active Crohn's disease of the ileum, right colon, or both. Patients were randomized to receive oral ciprofloxacin and metronidazole, both 500 mg twice daily, or placebo for 8 weeks. All patients received oral budesonide 9 mg once daily. The primary efficacy measure was the proportion of patients in remission at week 8. RESULTS Of the 134 patients who were randomized, 130 were evaluated for efficacy; 66 received placebo, and 64 received antibiotics. At week 8, 21 patients (33%) assigned to antibiotics were in remission as compared with 25 patients (38%) in the placebo group (P = 0.55; absolute difference, -5%; 95% confidence interval, -21% to 11%). An interaction (P = 0.025) between treatment allocation and disease location on treatment response was identified. Among patients with disease of the colon, 9 of 17 (53%) were in remission after treatment with antibiotics, compared with 4 of 16 (25%) of those who received placebo (P = 0.10). Discontinuation of therapy because of adverse events occurred in 13 of 66 (20%) patients treated with antibiotics, compared with 0 of 68 in the group who received placebo (P < 0.001). CONCLUSIONS In patients with active Crohn's disease of the ileum, the addition of ciprofloxacin and metronidazole to budesonide is an ineffective intervention, but this antibiotic combination may improve outcome when there is involvement of the colon.
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Seegers D, Bouma G, Peña AS. Review article: a critical approach to new forms of treatment of Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 2002; 16 Suppl 4:53-8. [PMID: 12047261 DOI: 10.1046/j.1365-2036.16.s4.8.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Most patients with inflammatory bowel disease can be managed with conventional immunosuppressive therapy. The choice of agents to prevent relapses of inflammatory bowel disease must be based on efficacy, toxicity and cost. Studies in animal models of inflammatory bowel disease indicate that chronic intestinal inflammation results from enhanced immune responses to bacteria that are present normally in the lumen. Loss of tolerance, an abnormal function or defective healing of the mucosal barrier may all give raise to chronic intestinal inflammation. This hypothesis is the basis of new therapies aimed at either decreasing the levels of luminal bacterial antigens and/or selectively blocking detrimental mucosal immune responses. Anti-TNF is an example of this novel approach that is very effective in Crohn's disease. The use of biological therapy is costly, however, and the long-term complications are not yet known. The recent increase of tuberculosis in patients treated with anti-TNF indicates that careful monitoring is necessary. It is clear that the new forms of treatment may play an important role in tailoring the appropriate drug to a specific group of patients. However, for the time being, fine-tuning in the use of conventional immunosuppression is necessary. New knowledge in the pharmacogenetics of these compounds allows improvements to be made in their use. It is to be hoped that a critical approach in the use of current and future drugs, taking into account the advances in the aetiopathogenesis of inflammatory bowel disease, will contribute to the quality of life of patients with inflammatory bowel disease.
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Affiliation(s)
- D Seegers
- Department of Gastroenterology, Vrije Universiteit Hospital Medical Centre, Amsterdam, The Netherlands
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42
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Cabré E. [Indications for azathioprine treatment in inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2002; 25:319-26. [PMID: 11985804 DOI: 10.1016/s0210-5705(02)79028-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- E Cabré
- Servicio de Gastroenterología. Hospital Universitari Germans Trias i Pujol. Badalona. Spain.
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43
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Affiliation(s)
- Burton I Korelitz
- Section of Gastroenterology, Lenox Hill Hospital, New York University School of Medicine, New York 10021, USA
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44
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Abstract
Crohn's disease is a lifelong illness characterized by chronic recurrent flares. The precise etiology of Crohn's disease is unknown. However, it appears to involve an enhanced systemic immune response and intensified local intestinal mucosal inflammatory activity, mediated through various inflammatory cells and an array of proinflammatory cytokines. Corticosteroids have been the mainstay of treatment of Crohn's disease. The controlled trials of the National Cooperative Crohn's Disease Study and the European Cooperative Crohn's Disease Study established that corticosteroids were effective for the induction of remission in Crohn's disease for the duration of the studies (6-17 wk). However, corticosteroids have not been shown to have an impact on the maintenance of long term remission in patients with Crohn's disease. In addition, they are associated with a high potential for dependence and serious toxic side effects. Alternative classes of medical therapy for Crohn's disease, including modified corticosteroids and a group of new biological therapies, have proven to be efficacious in the management of active and/or quiescent Crohn's disease.
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Affiliation(s)
- Yu-Xiao Yang
- Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA
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45
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Abstract
This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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Affiliation(s)
- M Schwab
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
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46
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Hommes DW, van de Heisteeg BH, van der Spek M, Bartelsman JFWM, van Deventer SJH. Infliximab treatment for Crohn's disease: one-year experience in a Dutch academic hospital. Inflamm Bowel Dis 2002; 8:81-6. [PMID: 11854604 DOI: 10.1097/00054725-200203000-00002] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The aim of this study was to report the 1-year clinical experience with infliximab treatment for Crohn's disease (CD) in the Netherlands. All 73 CD patients receiving infliximab infusions were prospectively followed during 1 year after the drugs' registration in the Netherlands. Clinical response and adverse events were assessed for both active luminal disease as well as fistulous disease. A total of 212 infusions were administered to 57 patients with active luminal CD and 16 patients with fistulous CD. The mean duration between infusions was 60 days. In 17% of patients, adverse events were recorded, of which one was serious. The response rate was 81% in active luminal CD and 87% in fistulous disease. Response rates were highest in patients receiving concomitant methotrexate as maintenance therapy. Steroids could successfully be tapered off in 73% of responding luminal CD patients and 100% of responding CD patients with fistulae. Eleven patients showed a loss of response to continuous infliximab readministration. Our clinical experience with infliximab for active luminal and fistulous CD showed that the administration is safe, effective, and has high steroid-sparing efficacy. Higher response rates were seen with methotrexate as concomitant medication.
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Affiliation(s)
- Daan W Hommes
- Department of Gastroenterology and Hepatology, Academic Medical Center, C2-116, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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47
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Everts M, Kok RJ, Asgeirsdóttir SA, Melgert BN, Moolenaar TJM, Koning GA, van Luyn MJA, Meijer DKF, Molema G. Selective intracellular delivery of dexamethasone into activated endothelial cells using an E-selectin-directed immunoconjugate. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 168:883-9. [PMID: 11777986 DOI: 10.4049/jimmunol.168.2.883] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
In chronic inflammatory diseases, the endothelium is an attractive target for pharmacological intervention because it plays an important role in leukocyte recruitment. Hence, inhibition of endothelial cell activation and consequent leukocyte infiltration may improve therapeutic outcome in these diseases. We report on a drug targeting strategy for the selective delivery of the anti-inflammatory drug dexamethasone to activated endothelial cells, using an E-selectin-directed drug-Ab conjugate. Dexamethasone was covalently attached to an anti-E-selectin Ab, resulting in the so-called dexamethasone-anti-E-selectin conjugate. Binding of the conjugate to E-selectin was studied using surface plasmon resonance and immunohistochemistry. Furthermore, internalization of the conjugate was studied using confocal laser scanning microscopy and immuno-transmission electron microscopy. It was demonstrated that the dexamethasone-anti-E-selectin conjugate, like the unmodified anti-E-selectin Ab, selectively bound to TNF-alpha-stimulated endothelial cells and not to resting endothelial cells. After binding, the conjugate was internalized and routed to multivesicular bodies, which is a lysosome-related cellular compartment. After intracellular degradation, pharmacologically active dexamethasone was released, as shown in endothelial cells that were transfected with a glucocorticoid-responsive reporter gene. Furthermore, intracellularly delivered dexamethasone was able to down-regulate the proinflammatory gene IL-8. In conclusion, this study demonstrates the possibility to selectively deliver the anti-inflammatory drug dexamethasone into activated endothelial cells, using an anti-E-selectin Ab as a carrier molecule.
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Affiliation(s)
- Maaike Everts
- Department of Pharmacokinetics, Groningen University Institute for Drug Exploration, Groningen, The Netherlands.
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Persley K, Scherl E, Rubin P. Avoidance of steroids by the early use of infliximab and 6-mercaptopurine in an adolescent with active Crohn's colitis. Am J Gastroenterol 2001; 96:3444-5. [PMID: 11774971 DOI: 10.1111/j.1572-0241.2001.05380.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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49
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Baldassano RN. Anti-TNF therapies have eliminated the need for steroids in pediatric Crohn's disease: pro. Why use steroids if safer therapies are available? Inflamm Bowel Dis 2001; 7:338-41; discussion 345-6. [PMID: 11720326 DOI: 10.1097/00054725-200111000-00011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- R N Baldassano
- Center for Pediatric Inflammatory Bowel Disease, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 19104, USA
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50
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Legnani PE, Kornbluth A. Immunomodulator Therapy in Inflammatory Bowel Disease. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2001; 4:199-205. [PMID: 11469977 DOI: 10.1007/s11938-001-0032-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
6-Mercaptopurine and its prodrug counterpart, azathioprine, have proven efficacy in the induction and maintenance of remission, fistula closure, and steroid sparing in patients with Crohn's disease. Long-term follow-up has demonstrated the safety of the purine analogues, with no increased risk of malignancy. For patients with Crohn's disease intolerant or unresponsive to azathioprine or 6-mercaptopurine, methotrexate has emerged as an effective alternative. In patients with severe ulcerative colitis, intravenous cyclosporine is highly efficacious in the short term, and with the addition of azathioprine or 6-mercaptopurine to oral cyclosporine, long-term remission rates of 60% to 70% can be achieved. Azathioprine or 6-mercaptopurine therapy is effective in patients with steroid-dependent or steroid-refractory colitis and is valuable in maintaining remission. Neither methotrexate nor cyclosporine has been shown to be effective for maintenance therapy in patients with ulcerative colitis. Current data are insufficient to recommend routine use of genetic or enzymatic testing of thiopurine methyltransferase or measurements of blood 6-thioguanine metabolites to guide 6-mercaptopurine or azathioprine dosing.
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Affiliation(s)
- Peter E. Legnani
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
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