Smoking and asthma (effect on treatment)

1. Smoking and asthma (effect on treatment) George Kontopyrgias MD, FCCP Respiratory department, Metropolitan General Hospital

2. Smoking and asthma(effect on treatment) • Smoking asthma in numbers • Clinical features • Response to corticosteroids • Other drugs • Smoking cessation

3. Smoking and asthma(effect on treatment) • Smoking asthma in numbers • Clinical features • Response to corticosteroids • Other drugs • Smoking cessation

4. Smoking asthma in numbers Prevalence rates similar to general population 20 – 30% of asthma patients are active smokers 20 – 30% of asthma patients are former smokers 1/2 of asthma patients are active or former smokers Demoly P et al Eur Respir Rev 2009 SirouxV et al Eur Respir J 2000 Yun S et al Prev Med 2006

5. Smoking asthma in numbers Higher prevalence rates • Adolescents Tyc V et al Pediatrics 2006 • Developing countries • 35% of asthma patients in emergency departments (50% smoking makes their asthma worse) (4% smoking might have been the trigger) Silverman R et al Chest 2003

6. Smoking asthma in numbers USA 17 million Americans have asthma 30% of asthma patients are active smokers 5 million Americans smokers with asthma 60% have persistent asthma require 1 canister of inh CS / month $ 2.2 billion per year for inh CS Lazarus S et al AJRCCM 2007

7. Smoking and asthma(effect on treatment) • Smoking asthma in numbers • Clinical features • Response to corticosteroids • Other drugs • Smoking cessation

8. Clinical features • More severe symptoms Althuis et alJ Asthma 1999 SirouxV et al Eur Respir J 2000 • Poorer control Boulet L et al Can Respir J 2008 Demoly P et al Eur Respir Rev 2009 • Worse asthma-specific quality of life Eisner et al Nicotine Tob Res 2007

9. Clinical features Current smokers with asthma Less likely to attend asthma education programs Abdulwadud et al Resp Med 1997 Gallefoss et al ERJ 2000 Lack of self-management skills Acute asthma Radeos et al AJEM 2001 Chronic asthmaMarks et al ERJ 1997

10. Clinical features Accelerated loss of lung function Decline in FEV1 (4000 adults, 18-30 yrs, followed up for 10 yrs) In 10 yrs 8% FEV1 Apostol G et al AJRCCM 2002

11. Clinical features • Increased emergency department visits Boulet L et al Can Respir J 2008 • Increased rates of hospitalization Sippel J et al Chest 1999 • Increased mortality Marquette C Am Rev Respir Dis 1992

12. Smoking and asthma(effect on treatment) • Smoking asthma in numbers • Clinical features • Response to corticosteroids • Other drugs • Smoking cessation

13. Inhaled corticosteroids • ICSare recommended as 1st line treatment in international guidelines • The evidence for this recommendation is based on clinical trials in never smokers or ex-smokers • Some studies suggest that efficacy of corticosteroids is reduced in asthma patients that are active smokers

14. Inhaled corticosteroids 1st study questioning the efficacy of ICS to asthmatic smokers Pedersen B et al Am J Respir Crit Care Med 1996;153:1519-1529

15. Inhaled corticosteroids Randomized placebo controlled study 38 patients with mild asthma 21 non-smokers and 17 smokers Inh fluticasone 1 mg/day vsplacebo 3 weeks Chalmers Get al Thorax 2002;57:226-230

16. Inhaled corticosteroids P = 0.001 Inhfluticasone Greater increase in PEF in nonsmokers compared with smokers 27 L/min - 5 L/min Chalmers Get al Thorax 2002;57:226-230

17. Inhaled corticosteroids • Only in non smokers • Increase in PEF • Increase in FEV1 • Increase in PC20 • Decrease in sputum eosinophils • “active smoking impairs the efficacy of short term • inhaled corticosteroids” Chalmers Get al Thorax 2002;57:226-230

18. Inhaled corticosteroids Randomized controlled study (SMOG Trial) Mild to moderate asthma 44 non-smokers 39 smokers (7 pys) Inh HFA-beclomethasone 320 μg/day tb montelukast 10mg/day 8 weeks Lazarus S et al AJRCCM 2007;175:783-790

19. Inhaled corticosteroids Inh beclomethasone Increased FEV1 only in non-smokers Non -Smokers Smokers Lazarus S et al AJRCCM 2007;175:783-790

20. Inhaled corticosteroids Higher dose? Longer period of treatment? Randomized double blind, parallel group study 95 patients with mild asthma Inh beclomethasone 400 μg (19 smokers vs 28 non-smokers) Inh beclomethasone 2000 μg (21 smokers vs 27 non-smokers) 12 weeks Tomlinson J et al Thorax 2005;60:282-287

21. Inhaled corticosteroids Non smokers Smokers 12weeks mPEF non-smokers > smokers Tomlinson J et al Thorax 2005;60:282-287

22. Inhaled corticosteroids 400μg Non smokers better mPEF Non-smokers  less exacerbations 2000μg (same results smaller differences) Tomlinson J et al Thorax 2005;60:282-287

23. Inhaled corticosteroids Low doses are ineffective even for longer treatment Fail to reduce exacerbations Higher doses are more effective Safety issues !! Tomlinson J et al Thorax 2005;60:282-287

24. Oral corticosteroids Route of administration? Randomized placebo controlled study Asthma patients 26 non-smokers 10 ex-smokers 14 smokers Oral prednisolone 40 mg/day vs placebo 2 weeks Chaudhuri R et al AJRCCM 2003;168:1308-1311

25. Oral corticosteroids Improvement in FEV1 in non smokers but not in smokers 237ml 47ml Chaudhuri R et al AJRCCM 2003;168:1308-1311

26. Oral corticosteroids Improvement in Asthma Control Score in non smokers but not in smokers Chaudhuri R et al AJRCCM 2003;168:1308-1311

27. Oral corticosteroids Oral corticosteroids are not effective Partial responsein the group of ex-smokers Corticosteroid insensitivity is partially reversible? Chaudhuri R et al AJRCCM 2003;168:1308-1311

28. Inhaled corticosteroids START study (post hoc analysis) 492 smokers and 2432 nonsmokers Inhaled budesonide 400 μg or placebo 3 years O'Byrne et al Chest 2009;136:1514-1520

29. Inhaled corticosteroids • The rate of decline in FEV1 of smokers was greater than in non- smokers (placebo arm) • Inh budesonide could equallyattenuate the decline in FEV1 in smokers and in non-smokers • post hoc anlysis – no data about smoking intensity • patients could have concurrent therapy with inh or oral CS to achieve asthma control O'Byrne et al Chest 2009;136:1514-1520

30. Corticosteroid insensitivity A) Altered airway inflammation Increased neutrophils in sputum of smokers with asthma Chalmers G et al Chest 2001 Neutrophilia in the airways is associated with a poor response to inhaled corticosteroids in asthma Green R et al Thorax 2002

31. Corticosteroid insensitivity B) Altered α/β glucocorticosteroid receptor ratio Glucocorticosteroid receptor β variant has negative activity Oakley RJ et al J Biol Chem 1999 Smokers have decreased glucocorticoid receptor α/β ratio Livingston E et al J Allergy Clin Immunol 2004 More GR-β less glucocorticoid effectiveness

32. Corticosteroid insensitivity C) Reduced histone deacetylase 2 (HDAC2) activity Smoking  oxidative stress  ↓ HDAC2 activity  ↓antiinflammatory activity of GCS Barnes PJ Proc Am Thorac Soc 2009

33. Smoking and asthma(effect on treatment) • Smoking asthma in numbers • Clinical features • Response to corticosteroids • Other drugs • Smoking cessation

34. Other drugs Restore steroid sensitivity ? Combination therapy ? Effective drugs ? New drugs ?

35. Other drugs Restore steroid sensitivity Combination therapy Effective drugs New drugs

36. Theophylline

37. Theophylline Theophylline increases HDAC activity in alveolar macrophages in smokers Cosio B J Exp Med 2004;200:689–695

38. Theophylline Low dose theophylline increases HDAC activityand improves the anti-inflammatory effects of steroids during COPD exacerbations Cosio B Thorax 2009;64:424-429

39. Theophylline Double blind parallel group pilot study 68 asthmatic smokers • Inh beclomethasone 200 μg/day • tb theophylline 400 mg/day • Both treatments combined 4 weeks Spears et al Eur Respir J 2009;33:1010-1017

40. Theophylline Low dose theophylline added to beclometasone (mean concentration of theophylline = 4.3 mg/L) • Improvement in PEF • Improvement in ACQ score • Borderline improvement in preFEV1 Low dose theophylline alone (mean concentration of theophylline = 4.9 mg/L) • Improvement in ACQ score • No improvement in lung function “These results need to be confirmed in larger trials” Spears et al Eur Respir J 2009;33:1010-1017

41. Other drugs Restore steroid sensitivity Combination therapy Effective drugs New drugs

42. Combination therapy ICS + LABA Post hoc analysis of GOAL trial ICS + LABA VSICS Reduction in exacerbation rates with ICS+LABA in smokers Boushey et al J Allergy Clin Immunol 2005

43. Combination therapy Tiotropium as an add on therapy Comparable results forsmokers and non-smokers Iwamoto H et al Eur Respir J 2008

44. Other drugs Restore steroid sensitivity Combination therapy Effective drugs New drugs

45. Leukotriene receptor antagonists Smoking  dose related increase in urinary LTE4 Fauler J et al Eur J Clin Invest 1997 “Healthy” smokers  Increased 15-lipoxygenase activity in the airways Zhu J et al Am J Respir Cell Mol Biol 2002 Smoking  increase in urinary LTE4 YES in asthma patients NO in COPD NO in “normal” subjects Gaki E et al Respir Med 2007

46. Leukotriene receptor antagonists Randomized placebo controlled study (SMOG Trial) Mild to moderate asthma 44 non-smokers 39 smokers Inh HFA-beclomethasone 320 μg/day oral montelukast 10 mg 8 weeks Lazarus S et al AJRCCM 2007;175:783-790

47. Leukotriene receptor antagonists Non -Smokers Montelukast Increased morning PEF only in smokers Smokers Lazarus S et al AJRCCM 2007;175:783-790

48. Leukotriene receptor antagonists Non -Smokers Montelukast no effect on PC20 Smokers Lazarus S et al AJRCCM 2007;175:783-790

49. Leukotriene receptor antagonists Non -Smokers Montelukast no effect on sputum eosinophils Smokers Lazarus S et al AJRCCM 2007;175:783-790

50. Leukotriene receptor antagonists Efficacy and safety of montelukast in smokers with asthma ?