9/21/2014. Asthma and Smoking. Prof. Samir Khedr. Determinants of the therapeutic response in asthma: cigarette smoking.

Transcription

1 Asthma and Smoking Prof. Samir Khedr. Determinants of the therapeutic response in asthma: cigarette smoking. 1

2 The therapeutic response to corticosteroids depends on many factors: Poor adherence to treatment. Inadequate inhaler technique. Concomitant disease and misdiagnosis. Genetic profile. Different inflammatory cells phenotypes with the airways; such as neutrophilic and eosinophilic inflamation. Exposure to allergen. Infections Race The rare phenotype of corticosteroid resistant asthma. - The mentioned factors have all been implicated in reducing the efficacy of corticosteroid. Recently, the impact of smoking on corticosteroid responsiveness in asthma has been studied. 2

3 Cigarette and smoking Cigarette smoking is common in adults with asthma with prevalence rates 14% to 59%. High levels of smoking found in adults resulted in: 1. Hospital emergency admission with acute asthma and in those who have died from asthma. 2. Morbidity and mortality rates in cigarette smokers with asthma Vs. never smokers. 3. Asthmatic patients who are active smokers have severe symptoms and reduced health status Vs. non-smokers. 4. The decline in lung function over time is increased in smokers Vs. non smokers with asthma. 3

4 Clinical Effects Of Active Smoking in Asthma: Increased symptoms severity. Accelerated decline in lung function. Reduced health status. Increased visits to emergency departments with acute asthma. Increased admissions to hospital for acute asthma. Increased mortality following admission to hospital with near fatal asthma. Busselton health study found: Adult males with asthma had an average annual decline in the forced expiratory volume in 1s (FEV1) of 54 ml in smokers compared to 40 ml in never smokers. Current asthmatic smokers are more likely to visit an emergency department with and exacerbation of asthma. Smokers are less likely to use appropriate methods to manage both acute and chronic asthma. 4

5 - Cigarette smoking is a risk factor for admissions to hospitals for acute asthma in some, but not all studies. - The mortality rate 6 years after near fatal asthma attack is increased amongst smokers vs non smokers. - There is a conflicting evidence on whether cigarette smoking influences the risk of near fatal and fatal attacks of asthma. Evidence for corticosteroid insensitivity - Several studies have demonstrated a reduced therapeutic response to inhaled and oral corticosteroids in active cigarette smokers with asthma. - The first evidence to suggest that smokers with asthma display corticosteroid insensitivity, was obtained from a post hoc analysis of a clinical trial and outcomes measures were limited to nonsmokers with asthma and no improvement occurred in the current smoking group. 5

6 - Lung function and airway hyperresponsiveness improved in non smokers following treatment with inhaled corticosteroids whereas no significant changes were observed in smokers with asthma. - Corticosteroid insensitivity in smokers with asthma extends to oral preparations. - A randomized controlled crossover trial of smokers, ex-smokers and never smokers with asthma investigated the response to oral corticosteroids. - All subjects demonstrated reversibility of 15% or more in FEV1 following salbutlamol at baseline. 6

7 - The never smokers demonstrated significant improvement in prebronchodilator FEV1, morning PEF and Asthma control score following presnisolone, but no change was observed in the smokers with asthma. An improvement was also seen in asthma symptoms and use of rescue medications in non-smokers, but not in the smokers. - Further evidence of smoking-induced corticosteroid insensitivity has been produced by the means of subcutaneous vasoconstrictor response, a test designed to compare the potency of topical corticosteroids. Reduced skin blanching response to topically applied corticosteroids compared to non-smoking asthmatics suggesting insensitivity in this group 7

8 - Environmental tobacco smoke (ETS) : may also be of relevance to corticosteroid sensitivity in nonsmokers with asthma. - ETS has been found to in induce insensitivity to the therapeutic effects of inhaled corticosteroids in one study; that found improved symptoms and quality of life and reduced absenteeism from school was only evident among children not exposed to ETS at home. - These clinical studies together suggest that smokers with asthma display relative insensitivity to the beneficial effects of short- to medium corticosteroid treatment. - If smokers with asthma require high doses of inhaled corticosteroids to produce a beneficial response, then this puts the at increased risk of long term adverse effects from inhaled corticosteroid treatment. 8

9 - It is important to characterize patients carefully when studying smokers with asthma, as a case-mix including patients with chronic obstructive pulmonary disease (COPD) could lead to false conclusions. - The smokers recruited to the above studies were in general younger than individuals who are typically symptomatic due to (COPD) and had a long history of asthma, also they were required to demonstrate evidence of bronchial hyperreactivity to methacholine or reversibility following inhaled salbutamol 15% to help exclude COPD Patients. Mechanism of corticosteroid insensitivity Mechanism of corticosteroid insensitivity in smokers with asthma have not been established, but could be due to: 1. Alterations in airway inflammatory cell phenotypes. 2. Mediator release. 3. Transcription factors activation. 4. Glucocorticoid receptor(gr) function. 5. Histone deacetylase activity. 9

10 drug Relative efficacy in smokers Mechanism of action in smokers corticosteroids reduced Currently unexplained; possible mechanisms include airway inflamatory cell phenotyopes, changes in GR to ratio, And/or reduced histone deacetylase activity theophylline reduced Increased clearance of theophylline because if induction of the enzyme, cytochrome P450 in smokers Leukotriene receptor antagonists Some benefit Not studied Short and long acting -agonists Anti-muscarinics No known difference No known difference Not studied Not studied Inflammatory cell phenotypes, mediators and transcription factors Sputum neutrophils are raised in high intensity smokers with asthma, which may explain the insensitivity to treatment with corticosteroids. Sputum eosinophils, which are responsive to corticosteroids, are reduced in high intesity smokers with asthma. This also could explain the impaired therapeutic response to corticosteroids. Pro-inflammatory cytokines released from the inflammatory cells following exposure to cigarette smoke such as (IL)-4, (IL)-8 and TNF as well as (NO), which is present in high conc. In tobacco smoke 10

11 Inflammatory cell phenotypes, mediators and transcription factors The anti-inflammatory cytokine IL-10 production by T Lymphocytes is suppressed in smokers. Multiple constituents within cigarette smoke activate proinflammatory transcription factors including factor (NF- KB), AP-1 and signal transductions and activators of transcriptions factors (STAT). All of the above have been implicated in causing corticosteroid resistance. Glucocorticoid Receptors Corticosteroids reduce inflammation through the activation of cytoplasmic GRs, which are ligand-activated transcription factors. Translocation of GR into the nucleus can suppress or induce glucocorticoid target genes by directly bind to the glucocorticoid-responsive elements (transactivation) or by interacting with pro inflammatory transcription factors (transpression). 11

12 Glucocorticoid Receptors Corticosteroid insensitivity could be due to either a reduction in ligand activated Gr, or over expression of the nonfunctional GR subtypes. - A recent study determined the ratio of the GR to isoforms in peripheral blood mononuclear cells(pmbc) using western blotting in current smoker and non smoker with and without asthma. - The GR to ratio was found to be reduced in the smoking groups. - Downregulation of the 2-adrenergic receptor function by cigarette smoke. - Might also impair the ability of 2-agonists to potentiate the increased nuclear localization of GRs Histone deacetylase activity One of these mechanisms exploited by corticosteroids to reduce transcription of inflammatory genes is activation of HDAC Smokers have decreased HDAC2 activity in alveolar macrophages, possibly as a result of nitrosative stress. This may lead to increased inflammatory gene expression and reduced sensitivity to corticosteroids. Corticosteroid resistance in COPD and smokers with asthma has been populated to operate by this pathway. 12

13 Other potential mechanisms The access of inhaled corticosteroids to target cells in the airways of smokers with asthma could be impaired due to: Increased airway mucosal permeability. Excess mucus within the airways. Reduced deposition of drug within the lungs due to increased particle size of inhaled corticosteroids in the presence of tobacco smoke. These mechanisms cannot explain the reduced therapeutic airway response to oral corticosteroids. Management Corticosteroid insensitivity has important implications for the management of smokers with asthma. National and international guidelines recommend inhaled corticosteroids as the first choice anti-inflammatory treatment for all types of chronic asthma including mild persistent asthma. This recommendation may need to be modified for the treatment of asthmatic smokers in order to take account of the impaired clinical response to short- to medium- term treatment with low dose inhaled corticosteroids. The current management of smokers with asthma should involve smoking cessation. additional or alternative drugs need to be identified to treat those individuals who are unable to stop smoking. 13

14 Smoking cessation Smoking cessation is the only disease-modifying therapy available in the management of mild or moderate cases of COPD. Little has been published on the effects of smoking cessation in asthma. In a longer term study, a prospective cohort of smokers with asthma reported improvements in symptoms and bronchial hyperactivity after 4 months of smoking cessation. Smoking cessation smoking cessation has been shown to improve: Lung function. Asthma control. Airway inflammation in asthma as early as 6 weeks after smoking cessation. These results demonstrates that there is a reversible component to the harmful effects of smoking on the airways in asthma. The degree of improvement noted by smoking cessation far exceeds that of high-dose anti-inflammatory treatment, such as oral prednisolone 40mg daily for 2 weeks, which had no effect on lung function in smokers with asthma. 14

15 Smoking cessation The improvement in lung function could be due to: Removal of the acute bronchoconstricor effects of cigarette smoke. Reduction in the pro-inflammatory effects of cigarette smoke on the airways. It is possible that there is some restoration of corticosteroid sensitivity after smoking cessation. Smoking cessation could reduce the required dose of theophylline, as theophylline clearance is increased by % in smokers. Smoking cessation Despite the potential benefits of smoking cessation, in clinical practice, cessation rates are very low. Smoking cessation or abstinence for 6 months or longer is 2%. With additional medication: 1. Nicotine gum 8% 2. Nicotine transdermal patch 6%. 3. Nicotine nasal spray 12%. 4. Nicotine inhalator 8%. 5. Nicotine sublingual tablets 8%. 6. Bupropion (300mg/day S.R) 9% Availability of alternative medication for asthmatic smokers is essential. 15

16 Drug treatment What are the pharmacological options available for the treatment of smokers with asthma to compensate for their relative corticosteroid insensitivity? A: Unfortunately, as a result of their exclusion from drug trials, there are limited data on drug treatments in smoker with asthma. therefore there is a need for noval medications to be tested in smokers with asthma. Potential Drug Treatments for smokers with asthma. Low dose theophylline in combination with ICS. Long-acting 2-receptor agonist in combination with ICS. Leukotriene receptor antagonist. PPARγ Agonists. Macrolide antibiotics. TNF, LTB4, IL-8, antagonists. Antioxidants. 16

17 Drug Treatment Theophylline: 1. Increases the HDAC activity. 2. Has been demonstrated to turn off inflammatory gene transcription in vitro. 3. Has the ability to increase corticosteroid sensitivity in corticosteroid resistant cell lines and in alveolar macrophages from patents with COPD and experimental models. Cigarette smoking causes an increase in urinary cysteinyl leukotriene (LT)E4 production. LT receptor antagonists produce improvements in airway obstruction and inflammation in asthma and beneficial effects may occur in smokers with asthma Effect of Montelukast for treatment of asthma in cigarette smokers J Allergy Clin Immunol 2013 Slide 34 17

18 Key Conclusion Evidence suggests that corticosteroids have reduced efficacy for treatment of asthma in smokers. Because smoking induces cysteinyl leukotriene production, treatment with Singulair might be helpful in this population. Both montelukast and fluticasone were superior to placebo in this population; the difference between the 2 treatments was not statistically significant. Patients with a smoking history of less than 11 pack years tended to show more benefit with fluticasone, whereas those with a smoking history of greater than 11 pack years tended to show more benefit with montelukast Slide 35 Effect of montelukast for treatment of asthma in cigarette smokers (Conclusion) Patients with a smoking history of >11 pack years tended to show more benefit with Montelukast. In a population of asthmatic patients actively smoking cigarettes, both 10 mg/d montelukast and 250 mg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo Singulair is an essential tool in asthma management especially in treatment of asthma in cigarette smokers J Allergy Clin Immunol 2013; Slide 36 18

19 Drug Treatment LABA in combination with ICS, is highly effective in asthma. LABAs have an essential role to play in COPD. These two drugs demonstrated to interact at a molecular level to potentiate the suppression of inflammation. Peroxisome proliferator-activated receptor γ agonists show promise in treatment of asthma. At present, results are only available for animal asthma studies, but evidence shows: 1. Ani-inflammatory effects on airway inflamation. 2. Inhibition of inflammatory transcription factors such as NF- B. 3. Synergistic effects with LABA and corticosteroids. Drug Treatment Many noval compounds are currently investigated in the treatment of Asthma and COPD such as: Macrolide antibiotics downregulate IL-8 production, and some of their attributed actions could be mediated via their antiinflammatory effects. Drugs that antagonize the effects of mediators implicated in cigarette smoke-induced airway inflammation such as TNF, LTB4, IL-8, inducible NO and several chemokines have potential as anti-asthma too. Anti-oxidants as they have block oxidative stress and have demonstrated to reduce exacerbations in COPD. 19

20 High dose inhaled corticosteroids may overcome impaired sensitivity in smokers with asthma; however, this puts the patient at risk for long-term adverse effects from corticosteroids as discussed by Clearie et al. Regarding other options for smokers, the additions of lowdose S.R Theophylline may restore corticosteroid sensitivity and Leukotriene receptor antagonists could have beneficial effects. What then are the management options when treating smokers with asthma? First, smoking cessation should be strongly encouraged. Addition of SABA therapy Should symptomatic smokers at step 2 be treated by the addition of a low-to medium-dose inhaled corticosteroid or as proposed by Clearie et al with combination efficaccy? Physicians should be aware however, that shortterm benefits from inhaled corticosteroids my be impaired in smokers and that a step-up in therapy may be required at an early stage. GOAL Trail supports the use of combination therapy with an ICS and LABA at step 3 in preference to the use of high-dose inhaled corticosteroids alone in smokers with asthma. 20

21 summery Smokers display: 1. Insensitivity to the therapeutic effects of corticosteroids, the most effective treatment for asthma. 2. Discrepancy in asthma control. Smoking cessation should be encouraged in all asthmatic smokers. Benefits include improvement in lung function and asthma control. The mechanisms responsible for this relative corticosteroid resistance need to be identified so that relevant pathways can be targeted by new and existing treatments (NEED FOR NOVAL DRUGS). Stepping up treatment: Addition of LABA to ICS. 21

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