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Big numbers may do big results:do not we forget the patients?
Does Interferon gamma-1b therapy improve survival in IPF via an angiogenetic pathway?
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Irene Esposito, MD researcher Respiratory Department Federico II Medical School University, Marco Perrella, Alessandro Sanduzzi
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spsrni{at}libero.it Irene Esposito, et al.
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Dear Sir We read with interest the article concerning the metaanalysis on the interferon-gamma1b therapy during idiopathic pulmonary fibrosis (IPF) (1). The question about the effectiveness of that treatment in patients suffering from IPF represents an important problem, firstly because it is yet unclear the real impact of that therapeutic schedule on the natural history of the illness, secondly because that drug has some important adverse effects that may influence the lifestyle of the patients (1). A metaanalysis of multiple studies, when performed, may collect more patients having the same immunological and physiopathological characteristic, but previously appertaining to different study groups. In that case, a bigger number may produce better results, nevertheless which is the destiny of the patients who do not respond to the treatment? Why they are not sensible to the interferon therapy? A possible explanation of so different results in the published research studies seems to be related to the small number of patients. Nonetheless also in a metaanlisys a percentage of patients do not show any beneficial effect from interferon treatment. Indeed, that data might be related to the different events involved in the pathogenesis of the illness and so to the possible lack of interferon activity in some patients. It is our opinion that actually there are few evidences of the real target of interferon and considering the unclear pathogenesis of IPF as well as a wide response to the treatment that hypothesis should not seem impossible. As the authors reported the rationale of IFN is actually based on the observation of its natural property as inhibitor of fibroblast and profibrotic cytokines that are involved in IPF (1). Nevertheless, it has also been proposed that during the IPF a failure in mounting a proper interferon gamma related CXCR3/CXCR3 ligand response seems to occur and to be related to disease pathogenesis (2). In this case the treatment with interferon could not be adequate because the target (the chemochine receptor) may have some functional alteration or simply not to be sensible to IFN. That data would suggest that a further classification of the immune system status should be performed on patients suffering from IPF aimed to have a better categorization and so to find an effective treatment, avoiding unhelpful and difficult management of patients. In conclusion, we would like to invite the scientific community to reflect also on the possibility of different pathways in the pathogenesis of IPF not related to IFN and having different possible management. That input should be stimulate new approaches to the treatment of IPF contemporary to the clinical trials on interferon, to improve the survival of the patients who do not respond to actual therapeutic schedule. References 1. Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-{gamma}1b Therapy in Idiopathic Pulmonary Fibrosis: A Metaanalysis. Chest. 2005;128:203-206 2. Strieter R.M. and Keane M.P. Innate immunity dictates cytokine polarization relevant to the development of pulmonary fibrosis. J Clin Invest. 2004;114:165. |
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DEMOSTHENES E BOUROS, PROFESSOR OF PNEUMONOLOGY DEPT.OF PNEUMONOLOGY, UNIVERSITY OF THRACE, ALEXANDROUPOLIS,GREECE, Katerina M. Antoniou, Nikolaos M. Siafakas, Demosthenes E. Bouros
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bouros{at}med.duth.gr DEMOSTHENES E BOUROS, et al.
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Dear Editor, We have read with particular interest the metaanalysis by Bajwa et al. (1) about the effects of interferon-gamma-1b (IFN-gamma-1b) therapy in Idiopathic Pulmonary Fibrosis (IPF). The conclusion of this study is that IFN-gamma-1b is associated with reduced mortality (1). As our preliminary data are included in this metaanalysis (2), we want to provide latest data after the end of our study (3). The purpose of this observational, randomized, prospective, multicenter study was to characterize the clinical effects of IFN-gamma-1b (200 mg) administered subcutaneously thrice weekly versus colchicine (1mg/day) for two years (3). Fifty consecutive IPF patients were randomized. Patients with mild- moderate IPF were eligible for the study if they had histologically proven IPF or, in the absence of surgical biopsy, fulfillment of the ERS / ATS criteria. Vital status was ascertained in all 50 randomized patients at the time of study completion. In the intent-to-treat population, 5 of 32 (15.6%) IFN-gamma-1b patients and 7 of 18 (38,8%) colchicine patients died (p=0.028) after a median period of follow-up of 25 months. In conclusion, if the above data are going to be included in the metaanalysis should definitely strengthen the therapeutic effect of IFN- gamma-1b in survival improvement. The emergent question from the above knowledge is the potential mechanism of action of this pleiotropic cytokine on survival of IPF patients. A recently published study (4) found changes after IFN-gamma-1b treatment primarily in angiogenic biomarkers (interferon –inducible T-cell -alpha chemoattractant, ITAC/CXCL11 and epithelial neutrophil–activating protein-78, ENA-78), but not in transforming growth factor-beta (TGF-beta) or connective tissue growth factor (CTGF), suggesting that IFN-gamma-1b may affect IPF through the angiogenesis pathway. In addition, ITAC/CXCL11 and two more interferon-inducible angiostatic chemokines (IFN- gamma -inducible protein of 10 kDa, IP-10/CXCL10 and monokine induced by IFN- gamma , MIG/CXCL9) demonstrated defensin-like antimicrobial activity (5), highlighting the potential role of IFN-gamma in regulation of one more pathway. We recently found an imbalance in the angiogenetic activity of IPF patients, in agreement with the above data (6). The bronchoalveolar lavage fluid (BALF) levels of three CXC chemokines with angiogenic activity (IL-8/CXCL8, ENA-78/CXCL5 and GRO-á) were significantly increased in IPF patients in comparison with the healthy controls. Furthermore, the levels of the above angiogenic chemokines significantly decreased after 12 months of IFN-gamma-1b treatment in 20 IPF patients (6). We suggest that long term treatment with IFN-gamma-1b improves survival particularly in patients with mild-moderate IPF. Our current hypothesis is that mortality in IPF could be potentially affected by this multifunctional cytokine through a down-regulation of the angiogenic pathway. REFERENCES 1. Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-{gamma}1b Therapy in Idiopathic Pulmonary Fibrosis: A Metaanalysis. Chest. 2005;128:203-206 2. Antoniou KM, Polychronopoulos V, Dimadi M, et al. Comparison of interferon ã-1b and colchicine in the treatment of idiopathic pulmonary fibrosis: preliminary results of a prospective, multicenter randomized study. American Thoracic Society 2003, 99th International Conference; May 16-21, 2003; Seattle, WA 3. Antoniou KM, Nicholson AG, Tzanakis N, et al. Long term clinical effects of interferon-gamma-1b and colchicine in idiopathic pulmonary fibrosis. Eur Respir J; under revision 4. Strieter RM, Starko KM, Enelow RI, Noth I, Valentine VG. Idiopathic Pulmonary Fibrosis Biomarkers Study Group: Effects of interferon gamma-1b on biomarker expression in idiopathic pulmonary fibrosis patients. Am J Respir Crit Care Med 2004; 170: 133-140 5. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RMCutting edge: IFN-inducible ELR- CXC chemokines display defensin-like antimicrobial activity. J Immunol 2001;167: 623-7 6. Antoniou KM, Tzortzaki EG, Tzanakis N, et al. Decreased levels of CXC Angiogenic Chemokines (IL-8, ENA-78 and GRO-á) in BALF after interferon gamma-1b treatment in IPF patients. ERS 15th Annual Congress: 17-21 September 2005, Copenhagen |
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1b Therapy in Idiopathic Pulmonary Fibrosis: A Metaanalysis
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