CONTROVERSIES AROUND USE OF CORTICOSTEROIDS IN COPD

Peter Barnes National Heart & Lung Institute Imperial College, London, UK
Amsterdam: September 2011

Imperial College

Royal Brompton Hospital

ASTHMA AND COPD

ASTHMA COPD

Airway Inflammation
Mast cells Eosinophils Inflammatory gene expression NF-B AP-1 Macrophages Neutrophils

Th2 cells

Tc1 cells

Steroid sensitive

Steroid resistant

TRIAL OF STEROIDS
500

Peak flow (L/min)

400 300 200 100 0

ASTHMA
Prednisolone 30 mg o.m. x 14 days

10

11

12

13

14

Days
Peak flow (L/min)
500 400 300

COPD
Prednisolone 30 mg o.m. x 14 days

200 100 0

10

11

12

13

14

OVERLAP BETWEEN COPD AND ASTHMA

COPD
Neutrophils No AHR No steroid response ~10%

ASTHMA
Eosinophils AHR Steroid response

Wheezy bronchitis

 EX NO & SPUTUM EOS IN REVERSIBLE COPD

Reversible: >15% in FEV1 after b/d Sputum eos

Exhaled NO

Papi A et al: AJRCCM 2000

EFFECT OF ORAL STEROID ON INDUCED SPUTUM INFLAMMATORY CELL PROFILE IN COPD

80 70

COPD patients (n=8) 645.1yr; FEV1=48% predicted

FEV1=1.20L FEV1=1.27L FEV1=1.30L
Macrophages Neutrophils Eosinophils

60 50
40 30 20 10 0

Baseline
Keatings V et al: AJRCCM 1997

Placebo

Prednisolone
(30mg daily x 14d)

EFFECT OF ICS ON FREQUENCY AND SEVERITY ON EXACERBATIONS

Fluticasone propionate (76/142) 75 Placebo No overall reduction in exacerbations (111/139) Small reduction in patients with
50

severe exacerbations

Exacerbations (%) ALTHOUGH

25

STATISTICALLY SIGNIFICANT IS THIS CLINICALLY RELEVANT ? *

0

Mild
Paggiaro P et al, Lancet 1998

Moderate

Severe Unknown

ICS AND ACUTE EXACERBATIONS

Several studies show a small reduction (25-25%)

in exacerbations - hospital admissions, oral steroids, antibiotics

Similar reduction is shown with long-acting bronchodilators

esp tiotropium bromide (LAMA) N.B. tiotropium has no anti-inflammatory effect in COPD

TIOTROPIUM vs SERETIDE: INSPIRE STUDY

COPD patients: FEV1 ~40% predicted: 2 years
1.5

N.S.

Exacerbations/year

Total
p<0.05

1
p<0.05

Oral steroids Antibiotics

0.5

Tiotropium (n=658)

Salmeterol/fluticasone (n=665)

Wedzicha JA et al: AJRCCM 2007

ICS AND ACUTE EXACERBATIONS

Several studies show a small reduction (25-25%)

in exacerbations - hospital admissions, oral steroids, antibiotics

Similar reduction is shown with long-acting bronchodilators

esp tiotropium bromide (LAMA) N.B. tiotropium has no anti-inflammatory effect in COPD

No additive effect of LAMA and ICS in exacerbations

Choice should therefore be based on long-term safety

ICS AND COPD PROGRESSION

TRIAL n DURATION SEVERITY
3 yr 3 yr 3 yr mild mild moderate

OUTCOME
no effect

Copenhagen City 290 EUROSCOP ISOLDE 1277 751

no effect
no effect no effect

Lung Health 2 1116 3.5 yr moderate 1o outcome = decline in lung function

Cochrane Database Systematic Review: >13,000 COPD patients- no FEV1 decline (Yang IM et al 2007)

18

ICS AND COPD MORTALITY

Probability of death (%)

16 14 12 10 8 6 4

TORCH STUDY
All cause mortality

16.0% 15.2% 13.5% 12.6%

No effect on mortality: 9 studies 17.5% OR 0.98 (0.83-1.16) n=8390 p=0.52

Yang IM et al: Cochrane review 2007

2
0 0 12 24 36 48 60

Placebo

Salm

FP

FP/Salm

72

84

96

108 120

132 144 156

Time to death (weeks)

Calverley PA et al: NEJM 2007

DOSE-RESPONSE TO INHALED STEROID IN ASTHMA

Change in FEV1 (litre)

compared to baseline

NO DOSE-RESPONSE TO nINHALED n=8 n = 20 n=6 =3 N = 1219 N = 3527 N = 872 N = 414 STEROIDS HAS BEEN 0.6 DEMONSTRATED IN COPD
0.4

0.2

IT IS DIFFICULT TO SHOW A 0.0 DOSE100 EFFECT WHEN THERE IS 200 500 1000 NO RESPONSE ! Daily dose of fluticasone propionate (g/day)

Adams NP & Jones PW: Resp Med 2006

INHALED CORTICOSTEROIDS IN COPD: SIDE EFFECTS

High doses usually used High risk of osteoporosis and fractures low mobility, poor nutrition, smoking, elderly Risk of cataracts

Co-morbidity may be worsened diabetes, hypertension, peptic ulceration]

Increased risk of pneumonia, TB

SIDE EFFECTS OF ICS IN COPD

47 studies in 13,139 patients oropharyngeal candidiasis OR 2.49 (1.78-3.49) n=4380 hoarseness NO major effect on fractures or BMD over 3 years
Yang IA et al, Cochrane review 2007

16-44% risk of cataracts with ICS exposure dose-response, observational study

Ernst P et al: ERJ 2006

Longer term studies are needed

TORCH STUDY: PNEUMONIA

25
p < 0.001 vs placebo

Probability of event (%)

20
15 10 5 0

SALM/FP 19.6% FP 18.3% SALM 13.3% Placebo 12.3%

12

24

36

48 60 72 84 96 108 120 132 144 156 Time to event (weeks)

Calverley PMA et al, NEJM 2007

PNEUMONIA: ICS+LABA vs LABA

OR 1.62 (1.35 to 1.94)

Nannini LJ et al: Cohrane Review 2007

ICS AND PNEUMONIA IN COPD

Nested case control study within population cohort from Quebec Healthcare Database covering >7 million 175,906 COPD patients (identified by Rx) - 7.1 y av. follow up 23,942 hospitalised for pneumonia (mean age 77yr) 4 controls /case Pneumonia rate (all) FP >1000 g/d Pneumonia death FP >1000 /d
Ernst P et al: AJRCCM 2007

RR on ICS 1.7 (1.63-1.77) 2.25 (2.07-2.44)

1.53 (1.30-1.80) 1.78 (1.33-2.37)

CYTOKINES IN INDUCED SPUTUM IN COPD: LACK OF EFFECT OF INHALED CORTICOSTEROID

COPD patients (n=14): age 65 1.1 yr; FEV1 = 35 1.3% Baseline
10 8

Placebo

Budesonide (800 g b.d.x 2 wk)

8

TNF-

[IL-8 (nmol/mL)]

N.S. 6 RESISTANCE MECHANISM IN COPD?

4
2 0 4

IL-8 IS THERE AN ACTIVE STEROID N.S.

2 0

Keatings V et al: Am J Respir Crit Care Med 1997

REDUCED EFFECT OF CORTICOSTEROIDS IN COPD

Bronchoalveolar lavage macrophages
200

Non-smoker

MIP-1 (ng/ml)

ALVEOLAR MACROPHAGES ARE STEROID-RESISTANT IN COPD (SIMILAR RESULTS WITH IL-8, MMP-9)

COPD

100

NS LPS

10-10

10-8

10-6

NS

LPS

10-8M

Dexamethasone (M)
Culpitt SV et al: Am J Respir Crit Care Med 2002

Dex

AMPLIFICATION AND STEROID RESISTANCE

Cigarette smoke

Corticosteroids

Oxidative stress

NF-B
Histone acetylation

Glucocorticoid receptor

HDAC2

Inflammatory genes
e.g. IL-8, MMP-9

Inflammation

AMPLIFICATION AND STEROID RESISTANCE

Cigarette smoke
3

Peripheral lung Theophylline

Nortriptyline

HDAC2 Oxidative stress

2

NF-B
Histone acetylation

PI3K-

Steroid resistance

HDAC2

Inflammatory genes
0e.g. IL-8, MMP-9

*** Inflammation

NonNormal COPD smokers smokers

Ito K et al: N Engl J Med 2005

INHALED CORTICOSTEROIDS IN COPD

Treat associated asthma

(asthma and COPD may coexist in the same patient)

No significant effect on inflammation (c.f. corticosteroids recommended for Inhaled asthma) patients with on progression of disease predicted) No effect severe disease (FEV1<50% whoReduction in severe exacerbations (small effect) have frequent exacerbations (>2/year) of patients (high dose ICS currently in >80%) <10% Risk of adverse systemic effects (esp diabetes) The use of high dose inhaled steroids for COPD Increased pneumonia, in needs to markedly reducedTB the future CanExpensive steroids more effective? we make Are there alternative anti-inflammatory treatments?

SO WHAT ABOUT INHALED STEROIDS IN COPD?

~80% diagnosed COPD patients in UK on ICS/combination

GOLD recommendations 10-20%!

Corticosteroids: NO anti-inflammatory effects in COPD in vitro

or in vivo (sputum, bronchial biopsies)

High dose ICS: no effect on FEV1 decline or mortality Small exacerbations: but trials misinterpreted

High dose ICS (FP): pneumonias systemic side effects with time
- osteoporosis, diabetes, cataracts, etc

Restrict use of ICS in the future?