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

Smoking and asthma (effect on treatment)

George Kontopyrgias MD, FCCPRespiratory department, Metropolitan General Hospital

Smoking and asthma(effect on treatment)

• Smoking asthma in numbers

• Clinical features

• Response to corticosteroids

• Other drugs

• Smoking cessation


• Smoking asthma in numbers

• Clinical featuresClinical features

• Response to corticosteroidsResponse to corticosteroids

• Other drugsOther drugs

• Smoking cessationSmoking cessation

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 2009Siroux V et al Eur Respir J 2000

Yun S et al Prev Med 2006


Higher prevalence rates

– AdolescentsTyc 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


USA17 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


• Smoking asthma in numbersSmoking asthma in numbers

• Clinical features




Clinical features

• More severe symptomsAlthuis et al J Asthma 1999

Siroux V et al Eur Respir J 2000

• Poorer controlBoulet 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

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 skillsAcute asthma Radeos et al AJEM 2001

Chronic asthma Marks et al ERJ 1997

Clinical features

Apostol G et al AJRCCM 2002

Decline in FEV1 (4000 adults, 18-30 yrs, followed up for 10 yrs)

Accelerated loss of lung function

In 10 yrs 8% FEV1

Clinical features

• Increased emergency department visitsBoulet L et al Can Respir J 2008

• Increased rates of hospitalizationSippel J et al Chest 1999

• Increased mortalityMarquette C Am Rev Respir Dis 1992




• Response to corticosteroids



Inhaled corticosteroids

ICS are 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


Pedersen B et al Am J Respir Crit Care Med 1996;153:1519-1529

1st study questioning the efficacy of ICS to asthmatic smokers


Randomized placebo controlled study

38 patients with mild asthma21 non-smokers and 17 smokers

Inh fluticasone 1 mg/day vs placebo

3 weeks

Chalmers G et al Thorax 2002;57:226-230



Inh fluticasone

Greater increase in PEF in nonsmokers compared

with smokers

27 L/min

- 5 L/min

P = 0.001



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”


Randomized controlled study (SMOG Trial)

Mild to moderate asthma44 non-smokers 39 smokers (7 pys)

Inh HFA-beclomethasone 320 μg/daytb montelukast 10mg/day

8 weeksLazarus S et al AJRCCM 2007;175:783-790


Lazarus S et al AJRCCM 2007;175:783-790

Smokers

Non -SmokersInh beclomethasone

Increased FEV1 only in non-smokers


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


12weeks

mPEF non-smokers > smokers

Non

smokers

Smokers



400400μμggNon smokers better mPEF

Non-smokers less exacerbations

20002000μμgg(same results smaller differences)



Low doses are ineffective even for longer treatment

Fail to reduce exacerbations

Higher doses are more effective

Safety issues !!


Oral corticosteroidsRoute 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

Oral corticosteroids


Improvement in FEV1

in non smokers

but not in smokers

47ml 237ml



Improvement in

Asthma Control Score

in non smokers

but not in smokers



Oral corticosteroids are not effective

Partial response in the group of ex-smokers

Corticosteroid insensitivity is partially reversible?


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


1. The rate of decline in FEV1 of smokers was greater than in non- smokers (placebo arm)

2. Inh budesonide could equally attenuate the decline in FEV1 in smokers and in non-smokers

O'Byrne et al Chest 2009;136:1514-1520

post hoc anlysis – no data about smoking intensity

patients could have concurrent therapy with inh or oral CS to achieve asthma control

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


B) Altered α/β glucocorticosteroid receptor ratio

Glucocorticosteroid receptor β variant has negative activityOakley RJ et al J Biol Chem 1999

Smokers have decreased glucocorticoid receptor α/β ratioLivingston E et al J Allergy Clin Immunol 2004

More GR-β less glucocorticoid effectiveness


C) Reduced histone deacetylase 2 (HDAC2) activity

Smoking oxidative stress ↓ HDAC2 activity ↓antiinflammatory activity of GCS

Barnes PJ Proc Am Thorac Soc 2009





• Other drugs


Other drugs

Restore steroid sensitivity ?

Combination therapy ?

Effective drugs ?

New drugs ?

Other drugs

Restore steroid sensitivity

Combination therapy Combination therapy

Effective drugs Effective drugs

New drugsNew drugs

Theophylline

Theophylline

Theophylline increases HDAC activity in alveolar macrophages in smokers

Cosio B J Exp Med 2004;200:689–695

Theophylline

Low dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids

during COPD exacerbations

Cosio B Thorax 2009;64:424-429

Theophylline

Double blind parallel group pilot study

68 asthmatic smokers

1. Inh beclomethasone 200 μg/day

2. tb theophylline 400 mg/day

3. Both treatments combined

4 weeks

Spears et al Eur Respir J 2009;33:1010-1017

TheophyllineLow dose theophylline added to beclometasone

(mean concentration of theophylline = 4.3 mg/L)

1. Improvement in PEF2. Improvement in ACQ score3. Borderline improvement in preFEV1

Low dose theophylline alone(mean concentration of theophylline = 4.9 mg/L)

1. Improvement in ACQ score2. No improvement in lung function

“These results need to be confirmed in larger trials”Spears et al Eur Respir J 2009;33:1010-1017

Other drugs

Restore steroid sensitivityRestore steroid sensitivity

Combination therapy


New drugs New drugs

Combination therapy

ICS + LABA

Post hoc analysis of GOAL trial

ICS + LABA VS ICS

Reduction in exacerbation rates with ICS+LABA in smokers

Boushey et al J Allergy Clin Immunol 2005

Combination therapy

Iwamoto H et al Eur Respir J 2008

Comparable results for smokers and non-smokers

Tiotropium as an add on therapy

Other drugs


Combination therapyCombination therapy

Effective drugs

New drugs New drugs

Leukotriene receptor antagonists

Smoking dose related increase in urinary LTE4Fauler 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 LTE4YES in asthma patientsNO in COPD NO in “normal” subjects

Gaki E et al Respir Med 2007


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



Smokers

Non -Smokers

MontelukastIncreased morning

PEF onlyin smokers



Smokers

Non -Smokers

Montelukastno effect on PC20



Smokers

Non -Smokers

Montelukastno effect on

sputum eosinophils



Efficacy and safety of montelukast in smokers with asthma ?

Other drugs


Combination therapyCombination therapy


New drugs

New drugs

Better Steroids (inhalers, safety profile)

Antioxidants

Target specific cells or mediatorsanti IL-8 (neutrophils)

anti IL-1β

anti TNFα

Target NF-κB

Better drugs for smoking cessation






• Smoking cessation

Smoking cessation

Ex-smokers with asthma (stopped for at least 1 year)Improvement in many symptoms (wheeze, cough)

Suzuki K J Asthma 2003

(27 out of 220 smoker asthmatics quit smoking for 4 months)

Reduce respiratory symptomsReduce airway hyperresponsivenessReduce need for rescue medication

Tonnesen et al Nicotine Tob Res 2005

Smoking cessation

Jang AS et al Allergy Asthma Immunol Res. 2010;2:254-259

10 quitters - asthma

22 smokers – asthma

Inh Fluticasone 1mg/day

3 months

% change FEV1

% change FEV1/FVC

Smoking cessation

Prospective, controlled study

Asthma patients 10 continue smoking VS 10 quit smoking

6 weeks


Smoking cessation


1. Improvement in lung function ( ↑ FEV1 407 ml after 6wks)2. Improvement in Asthma Control Score

Smoking cessation


3. Fall in sputum neutrophil count4. Better results than 40 mg prednisolone for 2 wks

Smoking cessation

Improved lung function (starting the 1st week)

Change in inflammatory pattern

Better asthma control


Smoking cessation

Conclusions

• Smoking cessation the best option• International guidelines

– Step-up in treatment is likely to be required at an earlier stage of the disease

– Higher doses of ICS– Leukotriene receptor antagonists– Theophylline

• We need more data from clinical trials

(older patients, overlap COPD and asthma)

Thank you

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

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