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      Withdrawal of inhaled corticosteroids in COPD patients: rationale and algorithms

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          Abstract

          Observational studies indicate that overutilization of inhaled corticosteroids (ICS) is common in patients with chronic obstructive pulmonary disease (COPD). Overprescription and the high risk of serious ICS-related adverse events make withdrawal of this treatment necessary in patients for whom the treatment-related risks outweigh the expected benefits. Elaboration of an optimal, universal, user-friendly algorithm for withdrawal of ICS therapy has been identified as an important clinical need. This article reviews the available evidence on the efficacy, risks, and indications of ICS in COPD, as well as the benefits of ICS treatment withdrawal in patients for whom its use is not recommended by current guidelines. After discussing proposed approaches to ICS withdrawal published by professional associations and individual authors, we present a new algorithm developed by consensus of an international group of experts in the field of COPD. This relatively simple algorithm is based on consideration and integrated assessment of the most relevant factors (markers) influencing decision-making, such a history of exacerbations, peripheral blood eosinophil count, presence of infection, and risk of community-acquired pneumonia.

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          Most cited references 51

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          Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.

          To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Double blind, placebo controlled study. Eighteen UK hospitals. 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.
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            Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

             Peter Barnes (2013)
            Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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              Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.

              Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 microg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 microg, budesonide 400 microg, formoterol 9 microg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (-7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                COPD
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                10 June 2019
                2019
                : 14
                : 1267-1280
                Affiliations
                [1 ]Department of Pulmonology, I.M. Sechenov First Moscow State Medical University , Moscow, Russian Federation
                [2 ]Clinical Department, Federal Pulmonology Research Institute, Federal Medical and Biological Agency of Russia , Moscow, Russian Federation
                [3 ]Department of Pulmonology, N.I. Pirogov Russian State National Research Medical University , Moscow, Russian Federation
                [4 ]Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education , Moscow, Russian Federation
                [5 ]Department of Phthisiology, Pulmonology and Thoracic Surgery, Ural State Medical University , Ekaterinburg, Russian Federation
                [6 ]Department of Internal Diseases No.1, I.M. Sechenov First Moscow State Medical University , Moscow, Russian Federation
                [7 ]Department of Differential Diagnostics, Federal Central Research Institute of Tuberculosis , Moscow, Russian Federation
                [8 ]Pneumology Department, University Hospital Vall d’Hebron/Vall d’Hebron Research Institute (VHIR), Ciber de Enfermedades Respiratorias (CIBERES) , Barcelona, Spain
                Author notes
                Correspondence: Sergey AvdeevDepartment of Pulmonology, I.M. Sechenov First Moscow State Medical University, Healthcare Ministry of Russia , Trubetskaya str., 8, Moscow119991, Russian FederationTel +7 495 708 3576Fax +7 495 395 6393Email serg_avdeev@ 123456list.ru
                Article
                207775
                10.2147/COPD.S207775
                6572750
                © 2019 Avdeev et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 1, Tables: 2, References: 75, Pages: 14
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