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Cantó E, Zamora C, Garcia-Planella E, Gordillo J, Ortiz MA, Perea L, Vidal S. Bacteria-related Events and the Immunological Response of Onset and Relapse Adult Crohn's Disease Patients. J Crohns Colitis 2019; 13:92-99. [PMID: 30247652 DOI: 10.1093/ecco-jcc/jjy138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Crohn's disease [CD] is a chronic, systemic inflammatory disease characterised by periods of remission and flare-ups. It has been associated with a disturbed gastrointestinal barrier function, an increase in the transport of luminal contents into the tissue, and lower immune tolerance. METHODS Peripheral blood samples were collected from healthy controls and 33 adult active flare-up CD patients. We classified patients as onset or relapse flare-up subjects, according to the days of disease evolution. Plasma levels of lipopolysaccharide-binding protein [LBP], fatty acid-binding proteins [FABP], and antibodies against bacterial lysates, interferons [IFN] and interleukin-6 [IL6] were measured by enzyme-linked immunosorbent assay [ELISA] in each group of patients. RESULTS Onset CD patients had higher plasma levels of LBP [57.32 ± 38.86 vs 30.22 ± 9.80 µg/ml] and IFNα [1.25 ± 0.23 vs 0.95 ± 0.36 log10pg/ml] and lower levels of immunoglobulins G and A [IgG and IgA] antibodies against bacterial lysates than relapse CD patients. We also observed a subgroup of onset patients with the highest levels of LBP. In this subgroup, LBP correlated negatively with C-reactive protein [CRP]. Onset and relapse CD patients had similar levels of FABP6 and FABP2, though LBP and FABP6 correlated positively only in relapse patients. In relapse patients, anti-E coli IgG antibodies correlated positively with systemic IL6 and IFNα levels. CONCLUSIONS Our findings suggest that onset and relapse flare-ups in adult CD patients are related to different systemic immune-related bacterial events. Characterising these differences may provide insights into the aetiology of Crohn's disease, and would help in the selection of appropriate therapies.
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Affiliation(s)
- Elisabet Cantó
- Department of Immunology, Biomedical Research Institute Sant Pau [IIB Sant Pau], Barcelona, Spain
| | - Carlos Zamora
- Department of Immunology, Biomedical Research Institute Sant Pau [IIB Sant Pau], Barcelona, Spain
| | - Esther Garcia-Planella
- Department of Digestive Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jordi Gordillo
- Department of Digestive Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - M Angels Ortiz
- Department of Immunology, Biomedical Research Institute Sant Pau [IIB Sant Pau], Barcelona, Spain
| | - Lidia Perea
- Department of Immunology, Biomedical Research Institute Sant Pau [IIB Sant Pau], Barcelona, Spain
| | - Silvia Vidal
- Department of Immunology, Biomedical Research Institute Sant Pau [IIB Sant Pau], Barcelona, Spain
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2
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Pott J, Stockinger S. Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology. Front Immunol 2017; 8:258. [PMID: 28352268 PMCID: PMC5348535 DOI: 10.3389/fimmu.2017.00258] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 02/21/2017] [Indexed: 12/19/2022] Open
Abstract
The intestinal mucosa forms an active interface to the outside word, facilitating nutrient and water uptake and at the same time acts as a barrier toward the highly colonized intestinal lumen. A tight balance of the mucosal immune system is essential to tolerate harmless antigens derived from food or commensals and to effectively defend against potentially dangerous pathogens. Interferons (IFN) provide a first line of host defense when cells detect an invading organism. Whereas type I IFN were discovered almost 60 years ago, type III IFN were only identified in the early 2000s. It was initially thought that type I IFN and type III IFN performed largely redundant functions. However, it is becoming increasingly clear that type III IFN exert distinct and non-redundant functions compared to type I IFN, especially in mucosal tissues. Here, we review recent progress made in unraveling the role of type I/III IFN in intestinal mucosal tissue in the steady state, in response to mucosal pathogens and during inflammation.
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Affiliation(s)
- Johanna Pott
- Sir William Dunn School of Pathology, University of Oxford , Oxford , UK
| | - Silvia Stockinger
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine , Vienna , Austria
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3
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Ferre Aracil C, Rodríguez de Santiago E, García García de Paredes A, Aguilera Castro L, Soria Rivas A, López SanRomán A. [Complete remission of Crohn's disease after high-dose alpha-interferon treatment for malignant melanoma]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 39:397-400. [PMID: 26096290 DOI: 10.1016/j.gastrohep.2015.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/29/2015] [Accepted: 05/04/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Carlos Ferre Aracil
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Madrid, España.
| | | | | | - Lara Aguilera Castro
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Ainara Soria Rivas
- Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal, Madrid, España
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Cho H, Kelsall BL. The role of type I interferons in intestinal infection, homeostasis, and inflammation. Immunol Rev 2015; 260:145-67. [PMID: 24942688 DOI: 10.1111/imr.12195] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Type I interferons are a widely expressed family of effector cytokines that promote innate antiviral and antibacterial immunity. Paradoxically, they can also suppress immune responses by driving production of anti-inflammatory cytokines, and dysregulation of these cytokines can contribute to host-mediated immunopathology and disease progression. Recent studies describe their anti-inflammatory role in intestinal inflammation and the locus containing IFNAR, a heterodimeric receptor for the type I interferons has been identified as a susceptibility region for human inflammatory bowel disease. This review focuses on the role of type I IFNs in the intestine in health and disease and their emerging role as immune modulators. Clear understanding of type I IFN-mediated immune responses may provide avenues for fine-tuning existing IFN treatment for infection and intestinal inflammation.
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Affiliation(s)
- Hyeseon Cho
- Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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5
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Levesque BG, Sandborn WJ, Ruel J, Feagan BG, Sands BE, Colombel JF. Converging goals of treatment of inflammatory bowel disease from clinical trials and practice. Gastroenterology 2015; 148:37-51.e1. [PMID: 25127678 DOI: 10.1053/j.gastro.2014.08.003] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Revised: 08/02/2014] [Accepted: 08/05/2014] [Indexed: 12/21/2022]
Abstract
It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn's disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn's Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration-sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of "treat-to-target" algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization.
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Affiliation(s)
- Barrett G Levesque
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
| | - Joannie Ruel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Brian G Feagan
- Robarts Clinical Trials, Robarts Research Institute, Department of Medicine, Western University, London, Ontario, Canada
| | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jean-Frederic Colombel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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6
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A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design. Inflamm Bowel Dis 2014; 20:1850-61. [PMID: 25029615 DOI: 10.1097/mib.0000000000000131] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. METHODS A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. RESULTS The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties. CONCLUSIONS Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.
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7
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Abstract
Over the past decade, much has been learned regarding the role of various cytokines in the pathogenesis of inflammatory bowel disease. Several cytokine ‘knockout’ models in mice have been shown to develop colitis, while alterations in the production of various cytokines has been documented in human Crohn's disease and ulcerative colitis. In recent years, attempts have been made to treat these diseases through modulation of cytokine production or action. This review focuses on the cytokines that have been implicated in the pathogenesis of inflammatory bowel disease. The evidence for and against a role for particular cytokines in intestinal inflammation is reviewed, as is the experimental and clinical data suggesting that cytokines are rational targets for the development of new therapies.
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Affiliation(s)
- P L Beck
- Intestinal Disease Research Unit Departments of Medicine and Pharmacology University of Calgary Alberta Calgary Canada
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8
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Dörffel Y, Swidsinski A, Loening-Baucke V, Wiedenmann B, Pavel M. Common biostructure of the colonic microbiota in neuroendocrine tumors and Crohn's disease and the effect of therapy. Inflamm Bowel Dis 2012; 18:1663-71. [PMID: 22113988 DOI: 10.1002/ibd.21923] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2011] [Accepted: 09/19/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND The aims were to comparatively investigate the biostructure of colonic microbiota in patients with neuroendocrine tumors and Crohn's disease (CD) and to study the response of the microbiota to therapy. METHODS Sections of fecal cylinders from 66 patients with neuroendocrine tumors (NET; 25 foregut, 30 midgut, 11 hindgut), 50 patients with CD (Crohn's Disease Activity Index [CDAI] ≥150), and 30 patients with chronic idiopathic diarrhea seen at the Charité Hospital and 25 healthy controls were investigated using fluorescence in situ hybridization with probes specific for five bacterial groups: Faecalibacterium prausnitzii, Clostridium group XIVa / Roseburia group, Bacteroides, Enterobacteriaceae, and Bifidobacteriaceae. RESULTS We found a striking F. prausnitzii (Fprau) depletion in the stool of patients with NET of the midgut and patients with CD. The changes of the microbiota in the two other NET groups were uncharacteristic and similar to those observed in patients with chronic idiopathic diarrhea. Fprau depletion was reversible with chemotherapy and with interferon alpha-2b treatment in patients with midgut NET. Somatostatin analogs had no influence on Fprau concentrations. CONCLUSIONS Patients with NET and CD show similarities in their abnormalities of the fecal biostructure. Interferon alpha and systemic chemotherapy significantly improved the fecal biostructure in patients with midgut NET.
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Affiliation(s)
- Yvonne Dörffel
- Outpatient Clinic, Internal Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
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9
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Abstract
The mucosal system is the first line of defense against many pathogens. It is continuously exposed to dietary and microbial antigens, and thus the host must maintain a homeostatic environment between commensal microbiota and pathogenic infections. Following infections and inflammatory events, a rapid innate immune response is evoked to dampen the inflammatory processes. Type I interferons, a family of pleiotropic cytokines and major products of the innate immune response, have a key role in these early immune events at the mucosa, as reviewed here. With the emergence of new discoveries of immune cell types in mucosal tissues and their reactions to commensal and pathogenic organisms, we also review the opportunities for exciting research in this field.
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10
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González-Navajas JM, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol 2012; 12:125-35. [PMID: 22222875 PMCID: PMC3727154 DOI: 10.1038/nri3133] [Citation(s) in RCA: 775] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.
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Affiliation(s)
- José M González-Navajas
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0663, USA.
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11
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Danese S, Angelucci E. New and emerging biologics in the treatment of inflammatory bowel disease: quo vadis? ACTA ACUST UNITED AC 2010; 33 Suppl 3:S217-27. [PMID: 20117345 DOI: 10.1016/s0399-8320(09)73157-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel diseases (IBD) are pathological conditions characterized by chronic inflammation that is primarily the consequence of dysregulation of the immune response. Over the last decade, the advances in the pathophysiology of IBD have paved the way for the development of a number of biological agents that selectively target specific molecules and/or pathways involved in gut inflammation. Although numerous, so far, the only biological therapeutics that are approved for the treatment for IBD are monoclonal antibodies against tumor necrosis factor alpha. This paper systematically reviews the mechanismof-action, efficacy, short-term and, where available, long-term safety of biological agents that target molecules other than tumor necrosis factor alpha, in IBD.
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Affiliation(s)
- S Danese
- Division of Gastroenterology, Istituto Clinico Humanitas, IRCCS in Gastroenterology, Rozzano, Milan, Italy.
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12
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Rodrigues S, Magro F, Soares J, Nunes ACR, Lopes S, Marques M, Rio E, Macedo G. Case series: ulcerative colitis, multiple sclerosis, and interferon-beta 1a. Inflamm Bowel Dis 2010; 16:2001-3. [PMID: 20186933 DOI: 10.1002/ibd.21242] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Katsanos KH, Tsianos VE, Zois CD, Zioga H, Vagias I, Zervou E, Christodoulou DK, Tsianos EV. Inflammatory bowel disease and hepatitis B and C in Western Balkans: a referral centre study and review of the literature. J Crohns Colitis 2010; 4:450-65. [PMID: 21122543 DOI: 10.1016/j.crohns.2010.03.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 02/28/2010] [Accepted: 03/01/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS There is limited data on IBD patients diagnosed with viral hepatitis B and C. The aim of the study was to assess the prevalence of chronic HBV or HCV infection in IBD patients followed by our centre and to describe and review the course of bowel and liver disease during therapy. METHODS Single centre retrospective study on 482 consecutive IBD patients. Laboratory investigation for HBV and HCV was performed with routine methods. Treatment protocols for HBV included IFNa and nucleot(s)ide administration and for HCV combined IFNa and ribavirin. RESULTS We diagnosed 15 patients (15/482, 3.1%) with HBV or HCV. Of these, 11 were HBV (11/482, 2.3%) and 4 were HCV (4/482, 0.8%). Nine of eleven HBV patients received antiviral therapy (8 lamivudine, 1 IFNa). Five lamivudine patients were switched to tenofovir and in another one adefovir dipivoxil were added. Bowel disease was in remission in ten of the eleven HBV patients. One patient was diagnosed with carcinoid tumor. Two HCV patients received IFNa that was well tolerated. One HCV patient denied therapy and one died from hepatocellular cancer. Of the seven patients on azathioprine only one achieved sustained response. Four patients on Infliximab achieved bowel disease remission but experienced biochemical or virological flare. CONCLUSIONS This study demonstrates that prevalence of HBV and HCV infection in a large IBD cohort from Western Balkans is compared to that of the background population. IBD patients under immunosuppressants may apparently be treated with safety if preventive antiviral treatment is administered.
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Affiliation(s)
- Konstantinos H Katsanos
- Hepato-Gastroenterology Unit & Laboratory of Immunology, 1st Division of Internal Medicine, Medical School of Ioannina, Greece
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Higashiyama M, Hokari R, Kurihara C, Ueda T, Nakamura M, Komoto S, Okada Y, Watanabe C, Kawaguchi A, Nagao S, Miura S. Interferon-α increases monocyte migration via platelet-monocyte interaction in murine intestinal microvessels. Clin Exp Immunol 2010; 162:156-62. [PMID: 20659125 DOI: 10.1111/j.1365-2249.2010.04222.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The aim of this study was to investigate the effect of interferon (IFN)-α on recruitment of platelets and monocytes within the murine small intestinal venular endothelium. Monocytes were isolated from bone marrow of C57B6 mice. Platelets were collected from murine blood. Rolling and adhesion to submucosal microvessels in the small intestine were examined under an intravital fluorescence microscope after injection of fluorescein-labelled monocytes or platelets. In some mice, IFN-α (5×10(5) U/kg) was administered intraperitoneally. After treatment with an antibody against P-selectin, changes in monocyte and platelet migration were also investigated. Changes in monocyte migration under the condition of thrombocytopenia were also investigated. Platelets and monocytes interacted with murine intestinal microvessels, although only few platelets and monocytes showed migration behaviour. Intraperitoneal injection of IFN-α enhanced the migration of both platelets and monocytes in the intestinal microvessels. Pretreatment with anti-P-selectin attenuated the increase in migration of platelets and monocytes induced by administration of IFN-α. Thrombocytopenia decreased the rolling ratio of monocytes, suggesting that the effect of IFN-α on migration was P-selectin-dependent, derived from both the endothelium of microvessels and platelets. The results of this study suggest that IFN-α acts as a potent proinflammatory agent via its stimulatory effect on the endothelium-platelet-monocyte interaction in intestinal microvessels by a P-selectin-dependent mechanism.
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Affiliation(s)
- M Higashiyama
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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Pena Rossi C, Hanauer SB, Tomasevic R, Hunter JO, Shafran I, Graffner H. Interferon beta-1a for the maintenance of remission in patients with Crohn's disease: results of a phase II dose-finding study. BMC Gastroenterol 2009; 9:22. [PMID: 19302707 PMCID: PMC2674451 DOI: 10.1186/1471-230x-9-22] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Accepted: 03/20/2009] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Crohn's disease (CD) and multiple sclerosis (MS) share common pathogenic processes. Interferon (IFN) beta-1a is effective and generally well tolerated in patients with MS and has been shown to down-regulate the expression of interleukin-12, a cytokine that is thought to be involved in mucosal degeneration in CD. IFN beta-1a therefore offers promise as a treatment for CD. METHODS In this multicentre, double-blind, placebo-controlled, phase II, dose-finding study, patients with steroid-induced clinical remissions of CD were randomized 1:1:1:1 to subcutaneous IFN beta-1a: 66 mcg three times weekly (tiw), 44 mcg tiw, 44 mcg twice weekly (biw), or matching placebo tiw with steroid tapering. The primary endpoint was the proportion of patients relapse-free at Week 26. Safety was also assessed. RESULTS This study was terminated early following a planned interim analysis at 26 weeks. Of the planned 192 patients, 67 were randomized to treatment: placebo (n = 16), or IFN beta-1a 44 mcg biw (n = 17), 44 mcg tiw (n = 16) or 66 mcg tiw (n = 18). In total, 20/67 patients (29.9%) completed 26 weeks and 7 patients (10.4%) completed 52 weeks. The proportion of patients who remained relapse-free at Week 26 did not differ significantly between the placebo group (5/16, 31%) and the IFN beta-1a 44 mcg biw (6/17, 35%; p = 0.497), 44 mcg tiw (7/16, 44%; p = 0.280) or 66 mcg tiw (2/18, 11%; p = 0.333) groups. There was little difference between treatment groups in secondary efficacy endpoints. IFN beta-1a was generally well tolerated at all doses. Adverse events (AEs) were generally mild or moderate in IFN beta-1a-treated patients, with the most common AEs (influenza-like symptoms, headache, injection-site reactions) being similar to those reported with IFN beta-1a in MS. CONCLUSION There was no difference in efficacy between patients with CD receiving IFN beta-1a or placebo. However, these results should be considered in the context of the low patient numbers and high dropout rate. Overall, IFN beta-1a was generally well tolerated, with a safety profile that was consistent with previous experience in MS. TRIAL REGISTRATION ClinicalTrials.gov NCT00304252.
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Affiliation(s)
- Claudia Pena Rossi
- Merck Serono S.A. – Geneva, 15bis, Chemin des Mines, CH-1211 Geneva 20, Switzerland
| | | | | | | | - Ira Shafran
- Shafran Gastroenterology Center, Winter Park, Florida, USA
| | - Hans Graffner
- Merck Serono S.A. – Geneva, 15bis, Chemin des Mines, CH-1211 Geneva 20, Switzerland
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16
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Scherzer TM, Staufer K, Novacek G, Steindl-Munda P, Schumacher S, Hofer H, Ferenci P, Vogelsang H. Efficacy and safety of antiviral therapy in patients with Crohn's disease and chronic hepatitis C. Aliment Pharmacol Ther 2008; 28:742-748. [PMID: 19145730 DOI: 10.1111/j.1365-2036.2008.03779.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Efficacy and safety of antiviral combination therapy in patients with Crohn's disease (CD) and chronic hepatitis C (CHC) is presently not established and consequently CHC is rarely treated in CD patients. AIM To analyse the efficacy and tolerability of antiviral interferon/ribavirin therapy in patients with CHC and CD. METHODS Eleven HCV-infected CD patients received either 3 x 1.5 microg/kg/week interferon-alpha-2b or 180 microg/week peginterferon-alpha-2a (PEGASYS; Roche, Basel, Switzerland) as monotherapy (n = 1) or in combination with 800-1200 mg/day ribavirin (COPEGUS; Roche) (n = 10) for 24-54 weeks according to HCV-genotype and initial response respectively. Eight patients were under CD-specific therapy. RESULTS Five (46%) patients (HCV-1: a = 3; HCV-2: n = 0; HCV-3: n = 1; unknown: n = 1) achieved a sustained virological response, three (27%) patients relapsed, three (27%) were nonresponders (all GT 1b). At baseline, the Harvey--Bradshaw Index was 0 (0-8) [median (range)], increased on antiviral therapy to 4 (1-15) (P = 0.005) and decreased to baseline level 0 (0-6) after 6-month follow-up. CONCLUSIONS This preliminary experience demonstrates that treatment of CHC in patients with CD is comparable to the treatment of CHC in those without CD. However, gastrointestinal symptoms may be temporarily exacerbated and haemopoietic growth factors may be required.
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Affiliation(s)
- T M Scherzer
- Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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Louis NA, Robinson AM, MacManus CF, Karhausen J, Scully M, Colgan SP. Control of IFN-alphaA by CD73: implications for mucosal inflammation. THE JOURNAL OF IMMUNOLOGY 2008; 180:4246-55. [PMID: 18322237 DOI: 10.4049/jimmunol.180.6.4246] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Inflammatory diseases influence tissue metabolism, altering regulation of extracellular adenine nucleotides, with a resultant protective influence of adenosine. Ecto-5'-nucleotidase (CD73) is a central surface enzyme generating extracellular adenosine. Thus, we hypothesized that CD73 is protective in mucosal inflammation as modeled by trinitrobenzene sulfonate (TNBS) colitis. Initial studies revealed a >3-fold induction of CD73 mRNA levels after TNBS colitis. Additionally, the severity of colitis was increased, as determined by weight loss and colonic shortening, in cd73(-/-) mice relative to cd73(+/+) controls. Likewise, enteral administration of the selective CD73 inhibitor alpha,beta-methylene ADP to cd73(+/+) mice resulted in a similar increase in severity of TNBS colitis. Gene array profiling of cytokine mRNA expression, verified by real-time PCR, revealed a >90% down-regulation of IFN-alphaA in cd73(-/-) mice and alpha,beta-methylene ADP-treated cd73(+/+) mice, compared with cd73(+/+) mice. Exogenous administration of recombinant IFN-alphaA partially protected TNBS-treated cd73(-/-) mice. Cytokine profiling revealed similar increases in both IFN-gamma and TNF-alpha mRNA in colitic animals, independent of genotype. However, IL-10 mRNA increased in wild-type mice on day 3 after TNBS administration, whereas cd73(-/-) mice mounted no IL-10 response. This IL-10 response was restored in the cd73(-/-) mice by exogenous IFN-alphaA. Further cytokine profiling revealed that this IL-10 induction is preceded by a transient IFN-alphaA induction on day 2 after TNBS exposure. Together, these studies indicate a critical regulatory role for CD73-modulated IFNalphaA in the acute inflammatory phase of TNBS colitis, thereby implicating IFN-alphaA as a protective element of adenosine signaling during mucosal inflammation.
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Affiliation(s)
- Nancy A Louis
- Neonatology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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18
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Schott E, Paul F, Wuerfel JT, Zipp F, Rudolph B, Wiedenmann B, Baumgart DC. Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferonβ 1a. World J Gastroenterol 2007; 13:3638-40. [PMID: 17659718 PMCID: PMC4146807 DOI: 10.3748/wjg.v13.i26.3638] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [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
To alert clinicians to a potential novel adverse drug effect of interferonβ 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferonβ 1a. Ulcerative colitis persisted despite discontinuation of interferonβ 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.
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Affiliation(s)
- Eckart Schott
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
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19
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Abstract
Several biologic agents have been assessed in patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC]). Until recently, only infliximab (humanized monoclonal anti-TNF-alpha antibody) had been approved by the Food and Drug Administration (FDA) to induce and maintain remission in patients with active mild to moderate and/or fistulizing Crohn's disease who are refractory to conventional therapy. Two recent trials, ACT 1 and ACT2, observed high efficacy of infliximab in inducing and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. This agent also was recently approved by the FDA for the treatment of ulcerative colitis to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa, and to eliminate the use of corticosteroids in patients with moderately to severely active UC who have had an inadequate response to conventional therapy. There have been many randomized, double-blind, controlled and open-label uncontrolled studies of large and small numbers of patients assessing the efficacy and safety of various biologic agents considered potentially useful in the treatment of IBD. Among all the biologic agents, infliximab has the most robust data on safety. This is because it has been evaluated in many more trials than has any other biologic agent. In addition, postmarketing experience provides very valuable information about adverse events occurring during treatment with this agent.
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Affiliation(s)
- Wojciech Blonski
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland
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20
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Abstract
PURPOSE OF REVIEW The purpose of this review is to analyze the complications associated with treatment of inflammatory bowel disease with biologic agents. RECENT FINDINGS There have been various biologic agents evaluated in patients with inflammatory bowel disease; that is, Crohn's disease and ulcerative colitis. Thus far only infliximab has been approved by the US Food and Drug Administration as induction and maintenance treatment in patients with active Crohn's disease (moderate-to-severe and/or fistulizing) who are refractory to conventional therapy. Recent data from two large multicenter, multicountry, randomized controlled clinical trials have demonstrated that infliximab is efficacious also for the treatment of ulcerative colitis. Other biologics considered potentially efficacious are still undergoing evaluation in various clinical trials. SUMMARY The data concerning biologics' associated toxicity in patients with inflammatory bowel disease are the most robust in the case of infliximab. These data are derived from both prospective, randomized clinical trials and from post-marketing experience. In the case of the remaining agents the data concerning safety in inflammatory bowel disease are limited, as these agents were not evaluated in as many trials as infliximab; indeed, some of them included only several patients.
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Affiliation(s)
- Wojciech Blonski
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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21
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Holtmann MH, Neurath MF. From immunogenic mechanisms to novel therapeutic approaches in inflammatory bowel disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 579:227-42. [PMID: 16620022 DOI: 10.1007/0-387-33778-4_15] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of chronic inflammatory bowel disease (IBD). The etiology of IBD is still unclear and should be considered as multi-factorial according to recent studies. Genetic factors seem to play a pathogenetic role as well as environmental, infectious and immulogical factors. Substantial progress, however, has been made in the understanding of the pathogenesis of IBD during the past years persuing the view, that IBD could result from disturbances of the intestinal barrier and a pathologic activation of the intestinal immune response towards luminal, bacterial antigens. This paradigm has led to the identification of key players of the intestinal immune system, which represent promising targets for novel therapeutic approaches. The objective of this chapter is to provide an overview over recent advances in the elucidation of the intestinal immune system in IBD and novel therapeutic approaches that have been derived from these results. Molecular biological techniques have revealed, that many of the established conventional antiinflammatory drugs such as salicylic acids, steroids or immunuosuppressants act at the same molecules that are the target for modern biologicals, i.e., the cytokine TNF or the transcription factor NFkappaB. This chapter, however, focusses on novel experimental approaches such as recombinant antiinflammatory cytokines, neutralizing antibodies or antisense oligonucleotides.
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Affiliation(s)
- Martin H Holtmann
- 1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany
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22
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Abstract
The medical management of patients with gastrointestinal diseases is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. Antisecretory approaches include drug combinations including a proton pump inhibitor, potassium competitive acid blockers, and antigastrin agents. The latter two classes are still experimental, but the former combinations have potential to enhance the highly effective agents currently available. The focus of treatment advances in chronic hepatitis C in the immediate future is the discovery of more effective treatment regimens for nonresponders to prior therapy, who are becoming the largest group of patients seeking treatment of hepatitis C. The combination of peginterferon with ribavirin results in 6%-15% sustained virologic response rates in patients who were prior nonresponders to standard interferon plus ribavirin. Newer strategies to eradicate hepatitis C virus infection using different interferons, such as interferon alfacon-1 or higher doses of peginterferon, or long-term maintenance peginterferon, are undergoing study and show promise based on data from preliminary studies. Several immunomodulators have promise in inflammatory bowel disease, although the risk-benefit ratio and costs of therapy require evaluation. Nevertheless, the success of new biologics such as anti-TNFalpha agents augurs well for effective future therapies.
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Affiliation(s)
- David C Metz
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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23
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Siveke JT, Folwaczny C. Biological response modifiers for the treatment of Crohn's disease. Expert Opin Biol Ther 2004; 4:1719-27. [PMID: 15500400 DOI: 10.1517/14712598.4.11.1719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Although standard medical therapy in Crohn's disease is efficient in most patients, a substantial proportion of patients suffering from chronic active disease do not adequately respond to standard therapy. In these patients, alternative regimens have to be considered. Due to the major advances in understanding the pathogenesis of this complex disease involving genetic, environmental, microbial and immunological factors, various new biological therapies targeting key mechanisms have emerged. In this review, a critical appraisal of modern therapeutical concepts will be presented, focusing on antibody and small inhibitory molecule therapies, including inhibition of TNF-alpha and other pro-inflammatory cytokines, adhesion molecules and T cell activation, as well as hormonal therapies.
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Affiliation(s)
- J T Siveke
- II. Med. Klinik, Klinikum rechts der Isar Technische Universität München, Germany
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24
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Tilg H, Kaser A. Type I interferons and their therapeutic role in Th2-regulated inflammatory disorders. Expert Opin Biol Ther 2004; 4:469-81. [PMID: 15102597 DOI: 10.1517/14712598.4.4.469] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cytokines are pleiotropic molecules showing a wide variety of biological functions on various cells and tissues. Several different cytokines exert similar and overlapping functions on certain cells. Interferons (IFNs) play a crucial role in human disease and consist of type I IFNs (IFN-alpha and IFN-beta) and type II IFN (IFN-gamma). The importance of type I IFNs in inflammation, immunoregulation and T cell responses has been recognised, and dendritic cells have recently been identified as the major source of type I IFNs. Type I IFNs are multifunctional immunomodulatory cytokines with profound effects on the cytokine cascade, including several anti-inflammatory properties. They favour both the induction of T helper (Th) 1 cytokines as well as the suppression of Th2 cytokines such as IL-13. Therefore, it is not unexpected that type I IFNs show promising clinical effects in Th2-dominated diseases such as ulcerative colitis and allergic asthma. These newly identified immunoregulatory and anti-inflammatory functions of type I IFNs may be of importance in the treatment of various chronic inflammatory disorders.
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Affiliation(s)
- Herbert Tilg
- Departmetn of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Austria.
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25
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Siveke JT, Folwaczny C. Medical approaches and future options in chronic active ulcerative colitis. Int J Colorectal Dis 2004; 19:297-307. [PMID: 14727131 DOI: 10.1007/s00384-003-0569-x] [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] [Accepted: 11/27/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND Immunosuppressive therapy employing purine analogues is the therapeutic mainstay in patients with chronic active ulcerative colitis. However, despite therapeutic optimization according to thiopurine-methyltransferase activity or red blood cell 6-thioguanine levels, a substantial proportion of patients does not tolerate azathioprine or 6-mercaptopurine or relapses during this treatment. In the latter multiple therapeutic regimens comprising 6-thioguanine, cyclosporin or tacrolimus, methotrexate, cyclophosphamide, infliximab, interferons, heparin, leukocyte apheresis, and various other regimens might be considered aiming at long-term remission. Many of these treatment forms have only been evaluated in small mostly uncontrolled trials. OBJECTIVE In this review existing treatment modalities and future options for patients with chronic active ulcerative colitis will be discussed focusing on immunomodulating approaches.
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Affiliation(s)
- J T Siveke
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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26
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Abstract
Autoimmunity appears to be a key factor in Crohn's disease as it develops in a genetically susceptible host if the immunological tolerance towards bacterial antigens within the gastrointestinal tract is abrogated. The resulting excessive immunological activity leads to a chronic sometimes transmural inflammatory process within the bowel wall. However, several lines of evidence are compatible with an immunodeficiency preceding these processes: humoral or cellular immune defects can predispose to inflammatory bowel disease. An increased bacterial adherence at the intestinal mucosa, which is possibly attributable to impaired expression of defensins was observed in Crohn's disease. Furthermore, the 3020insC mutation of the NOD2/CARD15 gene which is associated with Crohn's disease results in impaired cytokine transcription. Lastly, therapeutic approaches such as the use of antibiotic therapy or granulocyte macrophage colony stimulating factor are in line with the concept of an immunodeficiency being a crucial element in Crohn's disease.
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Affiliation(s)
- Christian Folwaczny
- Poliklinik der Universität, Standort Innenstadt, Ludwig-Maximilians Universität, Munich, Germany.
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27
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Abstract
PURPOSE To assess the role of endogenous interferon alpha (IFN) in auto-immune experimental models and human diseases, and to evaluate its iatrogenic potential as a therapeutic agent. MAIN POINTS IFN is a cytokine involved in cellular immunity, that promotes both differentiation of dendritic cells and the TH1 pathway. Auto-immune side-effects of recombinant IFN depend on IFN dosage and the pathology concerned. The spectrum extends from occurrence of auto-antibodies in an asymptomatic patient to overt disease such as systemic lupus. Antigenic targets of auto-antibodies are diverse: blood cells coagulation factors, immunoglobulin, hormones, intrinsic factor, intracellular components. Thyroiditis is the most frequently reported auto-immune disease occurring during IFN treatment, including hypothyroidism, hyperthyroidism or a bi-phasic pattern. Currently, true incidence of thyroiditis remains debated. It appears very low (under 1%) in hepatologic series using low-dose IFN. The fact that auto-immunity may be related to the treated disease--before use of IFN--must also be addressed: e.g. antinuclear factors and anti-DNA antibodies in chronic myeloid leukemia or anti-actin and anti-LKM antibodies in chronic C hepatitis. FUTURE PROSPECTS Recombinant alpha interferon appears more as a trigger than a de novo inducer of auto-immune disorders. Its use as an immunomodulator agent should be treated with caution.
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Affiliation(s)
- T Papo
- Service de médecine interne, hôpital Bichat, 46, rue Henri-Huchard, 75877 Paris, France.
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28
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Musch E, Andus T, Malek M. Induction and maintenance of clinical remission by interferon-beta in patients with steroid-refractory active ulcerative colitis-an open long-term pilot trial. Aliment Pharmacol Ther 2002; 16:1233-9. [PMID: 12144572 DOI: 10.1046/j.1365-2036.2002.01264.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The imbalance of pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of inflammatory bowel disease. Shifting this disturbed ratio by means of TNF-antibodies or interferon has been shown to be helpful in treating Crohn's disease and multiple sclerosis, respectively. AIM This pilot study investigated whether interferon-beta can induce clinical remission in corticoid-refractory ulcerative colitis. METHODS Twenty-five patients with steroid-refractory active ulcerative colitis (Clinical activity index according to Rachmilewitz: 13.5 +/- 5.2) were treated in an open pilot trial with 0.5 MIU human natural interferon-beta (hn-IFN-beta) i.v. (n=18) or 1 MIU recombinant interferon-beta-1a (r-IFN-beta-1-a) s.c. (n=7) daily with the goal of induction of remission. Subsequent maintenance treatment was carried out for 52.0 +/- 78.8 weeks (range 4-336 weeks) with the same dose, three times per week. RESULTS Twenty-two of 25 patients (88%) went into remission during induction treatment (hn-IFN-beta 16/18, r-IFN-beta-1a 6/7). Mean time to response was 3.0 +/- 1.3 weeks. Mean length of remission was 13.0 +/- 19.7 months. Only eight of 22 patients in remission relapsed during maintenance treatment. Five of these went into remission again after increasing the dose. Adverse events consisted of slight to moderate flu-like symptoms and slight to moderate hair loss in five of 15 female patients. CONCLUSION Although this open pilot study included only a small number of patients, the high response rate suggests that interferon-beta may be a safe and effective treatment for steroid-refractory active ulcerative colitis.
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Affiliation(s)
- E Musch
- Department of Internal Medicine, Marienhospital Bottrop, Germany.
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29
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Abstract
Advancing knowledge regarding the biology of chronic inflammation has led to the development of specific biologic therapies that mechanistically target individual inflammatory pathways. Many biologic therapies are being evaluated for the treatment of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Biologic compounds proven to be effective for Crohn's disease include monoclonal antibodies to tumor necrosis factor (infliximab and CDP571) and to the leukocyte adhesion molecule alpha4 integrin (natalizumab). Other biologic compounds for which there is insufficient evidence to judge efficacy for inflammatory bowel disease include: p55 tumor necrosis factor binding protein (onercept); interferon alpha; interferon beta-1a; anti-interferon gamma antibody; anti-interleukin 12 antibody; p65 anti-sense oligonucleotide (blocks NF-kappaB); granulocyte colony stimulating factor, and granulocyte macrophage colony stimulating factor; anti-interleukin 2 receptor antibody; epidermal growth factor; keratinocyte growth factor 2 (repifermin); human growth hormone; anti-CD4 antibody; and anti-alpha4beta7 antibody. Biologic therapies that have been proven ineffective for inflammatory bowel disease include: interleukin 10; interleukin 11; anti-sense intercellular adhesion molecule-1; and the tumor necrosis factor receptor fusion protein etanercept. Based on the early successes of infliximab, CDP571 and natalizumab, it seems certain that biologic therapy will play an important role in the future treatment of inflammatory bowel disease.
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Affiliation(s)
- William J Sandborn
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA.
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30
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Madsen SM, Schlichting P, Davidsen B, Nielsen OH, Federspiel B, Riis P, Munkholm P. An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis. Am J Gastroenterol 2001; 96:1807-15. [PMID: 11419834 DOI: 10.1111/j.1572-0241.2001.03875.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to compare the treatment efficacies of subcutaneous interferon-alpha-2A (IFN-alpha-2A) injections versus prednisolone enemas in active left-sided ulcerative colitis in an open-labeled, randomized study. METHODS Sixteen ulcerative colitis patients received IFN-alpha-2A subcutaneously (dosage: first wk, 9 MIU three times weekly [t.i.w.]; second wk, 6 MIU t.i.w.; wk 3-12, 3 MIU t.i.w.), and 16 received prednisolone enemas for 30 days (100 ml once daily, 0.25 mg of prednisolone/ml). The Powell-Tuck Index, Inflammatory Bowel Disease Questionnaire (IBDQ) score, and rectal histological activities were assessed before and after treatment. Thirteen patients in the IFN-alpha-2A group and all 16 in the prednisolone enema group completed the treatment. RESULTS IFN-alpha-2A treatment showed significant improvements in the Powell-Tuck Index (p = 0.0002), IBDQ score (p = 0.002), and rectal histological activity scores (p = 0.02). In the enema group, significant improvements were found in the Powell-Tuck Index (p = 0.0009), whereas no significant improvements were detected in the IBDQ scores (p = 0.055) or rectal histological scores (p = 0.052). There were no differences between scores of the two groups either before or after treatment. Only moderate side effects from the IFN-alpha-2A treatment were seen during the first 2-4 wk of treatment. CONCLUSION IFN-alpha-2A treatment resulted in significant depression of the disease activity as reflected by the Powell-Tuck Index, IBDQ score, and histological disease activity scoring. The preliminary trial thus suggests that IFN-alpha-2A may be effective in the treatment of active left-sided ulcerative colitis. Larger, randomized trials are, however, warranted to confirm this finding, owing to possible type II errors in group comparisons.
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Affiliation(s)
- S M Madsen
- Department of Medical Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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31
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Abstract
Looking back at successes and failures in newer approaches to treating IBD, it is tempting--although still difficult--to draw conclusions about pathogenesis. When a therapy proves effective, do clinicians truly know how it works? Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage. When a drug appears to be less effective than preclinical models suggest, can failures in effectiveness from delivery or dosing be differentiated? The disappointing results of clinical trials with IL-10--so at odds with the prediction of benefit from animal models--bring into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is judged. The variability of response even to the most narrowly targeted agents suggests that these diseases are far more heterogeneous in humans than in their murine counterparts. Clinicians are only just beginning to recognize subclinical markers of response, and it may soon be possible to predict response on the basis of genetic composition. For the moment, however, the field of pharmacogenetics is embryonic. Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level. Only through considered evaluation of clinical evidence may clinicians determine which therapies should remain novelties and which should become an accepted part of the armamentarium.
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Affiliation(s)
- B E Sands
- Harvard Medical School, Massachusetts General Hospital, Boston, USA
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32
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Järnerot G, Sandberg-Gertzén H, Tysk C. Medical therapy of active Crohn's disease. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1998; 12:73-92. [PMID: 9704156 DOI: 10.1016/s0950-3528(98)90086-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, extent and local complications of the disease as well as with the absence or presence of extraintestinal manifestations. Due to the troublesome consequences of the disease new treatments have continuously been tried. However, the results have varied and no definite breakthrough has occurred in the medical treatment of active Crohn's disease during the last years. The new salicylates have shown some effect using higher doses, but have not fulfilled the expectations once connected with their development. The new steroids have compared well to, but not exceeded, the older corticosteroid preparations in terms of therapeutic efficacy but they have a better side-effect profile. The role of the purine analogs azathioprine/6-mercaptopurine has been further evaluated. The onset of their effect is slow, an intravenous loading dose might shorten this time span, and they are steroid sparing. The controlled data on methotrexate are limited and the long-term effects not well studied and there is concern about toxicity. Even the use of cyclosporine in active Crohn's disease is controversial and connected with serious adverse events. Studies on the new immune modulating therapies such as anti-TNF-alpha antibodies, anti-CD4 antibodies, interleukin-10 and interferon have been encouraging but large scale studies are still awaited before the effect and the spectra of side-effects can be fully evaluated. The aim of this chapter is to summarize the present knowledge of medical treatment of active Crohn's disease and to point towards the directions of new therapeutic options.
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Affiliation(s)
- G Järnerot
- Department of Medicine, Orebro Medical Centre Hospital, Sweden
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Mire-Sluis AR, Page LA, Meager A, Igaki J, Lee J, Lyons S, Thorpe R. An anti-cytokine bioactivity assay for interferons-alpha, -beta and -omega. J Immunol Methods 1996; 195:55-61. [PMID: 8814320 DOI: 10.1016/0022-1759(96)00092-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Interferons-alpha and -beta (IFN-alpha and -beta) are cytokines that are widely known to induce potent anti-viral activity. However, it has become increasingly apparent that IFN-alpha and -beta exert a variety of other biological effects, including anti-tumour and immunomodulatory activities and are increasingly used clinically to treat a range of malignancies, myelodysplasias and autoimmune diseases, e.g., IFN-beta for multiple sclerosis. The most widely used bioassays for the IFNs are based on their anti-viral activity, but these do not predict the biological activity of the IFNs in anti-tumour and immunomodulatory therapies. Thus, we have developed anti-cytokine-based bioassays that may be more reflective of such activity and which have several advantages over existing anti-viral bioassays. The anti-cytokine bioassay is based on the ability of IFN-alpha, -beta and -omega to inhibit granulocyte-macrophage-colony-stimulating factor (GM-CSF) induced proliferation of the erythroleukaemic cell line TF-1. This assay can take only 24 h, is sensitive to 200 fg (0.04 IU) IFN-alpha or -beta and 100 fg (0.02 IU) IFN-omega and is able to detect down to these levels in serum or plasma samples. The usefulness of anti-cytokine bioassays for IFN-alpha, -beta and -omega is not restricted to the GM-CSF/TF-1 cell format and other alternatives are available, such as erythropoietin (EPO)/TF-1 cells and EPO/UT-7-EPO cells. These assays can be made specific for each of the IFNs by including neutralising antibodies in the bioassay.
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Affiliation(s)
- A R Mire-Sluis
- Division of Immunobiology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, U.K
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