Systemic Inflammation and Comorbidities in COPD COPDforum is supported by.

Systemic Inflammation and Comorbidities in COPD

COPDforum is supported by

2

Systemic Inflammation and Comorbidities in COPD

Systemic Inflammation

Comorbidities in COPD

– Skeletal Muscle Dysfunction

– Cardiovascular Disease

– Osteoporosis

– Anaemia of Chronic Disease

– Metabolic Abnormalities in COPD

– Depression

– Gastrointestinal Disease

Effects of COPD Treatment on Systemic Comorbidities

Systemic Inflammation

4

Systemic Inflammation in COPD

COPD is an inflammatory condition

Pro-inflammatory mediators may be the driving force behind the disease process

Inflammation and actions of pro-inflammatory mediators may extend beyond the lungs and play a part in COPD comorbidities

As effective anti-inflammatory therapy becomes available for COPD, it will be important to monitor the effects on lungs and associated comorbidities

Sevenoaks MJ, Stockley RA. Respir Res. 2006;7:70.

5

Systemic Inflammation in COPD:C-reactive Protein Is Elevated

Gan WQ, et al. Thorax. 2004;59:574-580. Copyright © 2004 BMJ Publishing Group Limited. All rights reserved.

Dentener

Eid

Mannino

Mendall

Yasuda

Pooled summary

Standardised mean difference of CRP

Greaterin controls

Greater in COPD

-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

6

——

—

5.03

2.022.24

0

1

2

3

4

5

6

COPD (N=88) Smokers without COPD (N=33)

Nonsmokers without COPD (N=38)

CR

P (

mg/

L)CRP Is Elevated in Patients With COPD versus Smokers and Nonsmokers

*

*P<0.05 versus other groups

Pinto-Plata VM, et al. Thorax. 2006;61:23-8.

7

Systemic Inflammation in COPD:TNF- Is Elevated

Gan WQ, et al. Thorax. 2004;59:574-580. Copyright © 2004 BMJ Publishing Group Limited. All rights reserved.

de Godoy

Yasuda

Pooledsummary

Standardised mean difference of TNF-alpha

Greaterin controls

Greater in COPD

-0.4 -0. 2 0.0 0.2 0.4 .06 .08 1.0 1.2 1.4

Di Francia

Takabatake

8

Systemic Inflammation in COPD: Fibrinogen Is Elevated

Gan WQ, et al. Thorax. 2004;59:574-580. Copyright © 2004 BMJ Publishing Group Limited. All rights reserved.

Alessandri

Engstrom (smokers)

Mannino

Pooled summary

Standardised mean difference of fibrinogen

Greaterin controls

Greater in COPD

1.6-0. 2 0.0 0.2 0.4 .06 .08 1.0 1.2 1.4

Dahl (smokers)

9

Systemic Inflammation in COPD: Elevated Leucocytes

Gan WQ, et al. Thorax. 2004;59:574-580. Copyright © 2004 BMJ Publishing Group Limited. All rights reserved.

Dentener

James (smokers)

Pooled summary

Standardised mean difference of leukocytes

Greaterin controls

Greater in COPD

2.0-0. 2 0.2 0.4 0.6 1.0 1.2 1.4 1.6 1.8

Mannino

0.0 0.8

10

—

—

Systemic Inflammation in COPD: Elevated VEGF

665.3

318.9

0

100

200

300

400

500

600

700

800

COPD Patients Normal Controls

Ser

um V

EG

F (

pg/m

L)

Kierszniewska-Stepien D, et al. Eur Cytokine Netw. 2006;17:75-79.

P<0.05P<0.05

11

Systemic Inflammation RisesWith COPD Severity

CRP TNF-

SevereCOPD

ModerateCOPD

MildCOPD

Healthy

0

Serum C-Reactive Protein (mg/L)

20 30 40 50 60 7010

SevereCOPD

ModerateCOPD

MildCOPD

Healthy

0 40 10060 8020

Serum TNF-Alpha (pg/mL)

Reprinted from Pulm Pharmacol Ther, Vol 19, Franciosi LG, et al, Markers of disease severity in chronic obstructive pulmonary disease, pp 189-199, Copyright 2006, with permission from Elsevier.

Comorbidities in COPD

13

Systemic Inflammation and Comorbidities

COPD

OSTEOPOROSISDIABETES

BODYCOMPOSITION

INFLAMMATION

Agusti AG, et al. Eur Respir J. 2003;21:347-360.Agusti A. Proc Am Thorac Soc. 2007;4:522-525.

CARDIOVASCULARDISEASE

GASTROINTESTINALDISORDER

14

COPD Increases Risk for Medical Events

Angina

Cataracts

Respiratory Infection

Myocardial Infarction

Fractures

Osteoporosis

Glaucoma

Skin Bruises

RR in COPD versus non-COPD

Rat

e pe

r 10

,000

4320 10

100

200

300

400

PneumoniaPneumonia

Reproduced with permission of Chest, from “Patterns of comorbidities in newly diagnosed COPD and asthma in primary care,” Soriano JB et al, Vol 128, pp 2099-2107, Copyright © 2005; permission conveyed through Copyright Clearance Center, Inc.

15

—

—

— ——

—

Higher Rates of Hospitalisation Due to Comorbidities in COPD

16.5

15

10.211

9.8

7

3 2.6

12.6

10.29.5

2.93.6

1.6 0.4 10

2

4

6

8

10

12

14

16

18

Hypertension IHD Diabetes Pneumonia CHF RF PVD TM

Pe

rce

nt o

f Su

bje

cts

COPD

No COPD

IHD = ischaemic heart diseaseCHF = congestive heart failureRF = respiratory failurePVD = pulmonary vascular diseaseTM = thoracic malignancy

— —

Reproduced with permission of Chest, from “Comorbidity and Mortality in COPDRelated Hospitalizations in the UnitedStates, 1979 to 2001,” Holguin F et al, Vol 128, pp 2005-2011, Copyright © 2005.

16

Death Due to Comorbidities Is More Common in COPD

37

25

22.5

19

1312

11

5

22

14

1012

8.56.5

10

3

0

5

10

15

20

25

30

35

40

RF Pneumonia Heart Failure IHD Hypertension TM Diabetes PVD

In H

osp

ital M

ort

alit

y (a

s %

of d

isch

arg

es)

COPD

No COPD

IHD = ischaemic heart diseaseCHF = congestive heart failureRF = respiratory failurePVD = pulmonary vascular diseaseTM = thoracic malignancy

Reproduced with permission of Chest, from “Comorbidity and Mortality in COPDRelated Hospitalizations in the UnitedStates, 1979 to 2001,” Holguin F et al, Vol 128, pp 2005-2011, Copyright © 2005.

17

Hospitalisations in Patients With COPD

0 2 4 6 8 10 12 14 16

Respiratory System

Cardiovascular System

Neoplasms

Endocrine Disorders

Nervous System

Digestive System

Genitourinary System

Musculoskeletal System

Controls (N=4,566)

COPD (N=1,522)

Mapel DW, et al. Arch Internal Med. 2000;160:2653-2658.

Hospital Discharges per 100 Patients

18

Systemic Inflammation in COPD:Potential Clinical Consequences

Skeletal muscle dysfunction Increased risk of cardiovascular disease and death Osteoporosis Anaemia of chronic disease Metabolic disease (e.g., diabetes mellitus) Depression Gastrointestinal disease

Agusti AG, et al. Eur Respir J. 2003;21:347-360. Chatila WM, et al. Proc Am Thorac Soc. 2008;5:549-555.Sevenoaks MJ, Stockley RA. Respir Res. 2006;7:70-78. Luppi F, et al. Proc Am Throrac Soc. 2008;5:848-856.

COPDforum is supported by

Skeletal Muscle Dysfunction

20

Skeletal Muscle Apoptosis in COPD

Healthy Subject COPD Patient

Nucleus of apoptotic muscle fiber

Agusti AG, et al. Am J Resp Crit Care Med. 2002;166:485-489. Copyright 2002 © American Thoracic Society. Material Adapted.

21

Fat-free Mass Is Reduced in COPD

Sergi G, et al. Respir Med. 2006;100:1918-1924.

49

50

51

52

53

54

55

COPD (N=40) No COPD (N=46)

Fat

-fre

e M

ass

(kg)

*

*P<0.05

50.750.7

53.953.9

22

COPD and Cachexia

Weight loss and muscle wasting are common in COPD

Increased breakdown of muscle proteins, a typical feature of cachexia, has been demonstrated in patients with COPD

– Patients with stable COPD have higher whole-body myofibrillar protein breakdown versus individuals without COPD

– Myofibrillar protein breakdown is an important target for intervention in patients with COPD

Rutten EP, et al. Am J Clin Nutr. 2006;83:829-834.

23

Systemic Inflammation and Muscle Wasting in COPD: Suggested Model

Sevenoaks MJ , Stockley RA. Respiratory Res. 2006;7:70-78.

Inflammatory Pathways Leading to Muscle Wasting

PROTEIN LOSSPROTEIN LOSS

ApoptosisApoptosis

↓MyoD gene expression↓MyoD gene expressionNF-D activationNF-D activation

↑Ubq/proteasome activity↑Ubq/proteasome activity ↓Muscle use;other local factors

↓Muscle use;other local factors

↓MYOFIBRILSYNTHESIS↓MYOFIBRILSYNTHESIS

↓↓IGF-1IGF-1↓↓IGF-1IGF-1

Circulating TNF-Circulating TNF-

TNF-R bindingTNF-R binding

↑ROS frommitochondria↑ROS from

mitochondria

24

Relationship Between Skeletal Muscle Mass and Inflammatory Markers in COPD

CHI = creatine height index, a measure of skeletal muscle mass, Normal CHI 80% predicted, Low CHI <80% predicted

2.83

2.22.4

4.554.2

3.2

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

CRP ( g/mL) IL-6 (pg/mL) TNF- (pg/mL)

Normal CHI

Low CHI

*

*

Eid AA, et al. Am J Respir Crit Care Med. 2001;164:1414-1418.

3.03-6.81

2.70-3.90

2.00-2.90

3.00-5.90

1.70-2.80

1.86-4.32†

*P<0.05 for between-group difference, † 95% CI

COPDforum is supported by

Cardiovascular Disease

26

Inflammation in Cardiovascular Disease

Available at: http://www.clevelandclinic.org/heartcenter/pub/news/hot/crp2.htm

Modified lipoproteinsHaemodynamic insultsReactive oxygen speciesInfectious agents

MCP-1M-CSFIL-8

Endothelial injury

ICAM-1

CRPmoiety

Macrophage

T lymphocyte More cytokinesGrowth factors Scavenger

receptorsOx-LDL

27

COPD Inflammation Can Contribute to Cardiovascular Disease

Rennard SI. Proc Am Thorac Soc. 2005;2:94-100. Permission requested.

Lung Inflammation

Chronic Acute

TNF-α

C-reactive Protein

Progressive Atherosclerosis

Autonomic Instability

Arrhythmias

IL-6

Fibrinogen

Coagulation

GM-CSF

Neutrophils

Inflammation

GM-CSF = granulocyte-macrophage colony stimulating factorIL = interleukin TNF = tumor necrosis factor

28

Risk for Cardiovascular Disease in COPD Patients and Matched Controls

Curkendall SM, et al. Am J Epidemiol. 2006;16:63-70.

21.1

11.2

5.6

31.3

9.6

70.4

22.8

11.7

6.43.2

9.0 7.9

54

11.2

0

10

20

30

40

50

60

70

80

Arrhythmia Angina Acute MI CHF Stroke Other CVD CVD Hospitalisation

Per

cent

of

Sub

ject

s

COPD (N=11,493)

Controls (N=22,986)

*

*

**

*

*

*

*P<0.05 for between-group difference

MI = myocardial infarctionCHF = congestive heart failureCVD = cardiovascular disease

MI = myocardial infarctionCHF = congestive heart failureCVD = cardiovascular disease

29

1.561.48

1.55

1.15

1.0

1.88

1.5

1.22

1.01 1.0

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

First Second Third Fourth Fifth

Re

lativ

e H

aza

rd R

atio

Men

Women

Risk for Ischaemic Heart Disease as a Function of Pulmonary Function

Hole DJ, et al. BMJ.1996;313:711-715.

FEV1 QuintileIncreasing FEV1

P<0.001 for trend in both men and women

1.68-2.20†

0.75-1.38

0.92-1.430.91-1.63

1.25-1.91

1.44-2.47

1.13-1.971.19-1.83

Reference

†95% CI

Increasing FEV1Increasing FEV1

30

1.66 1.65

1.16 1.16

1

1.651.54

1.311.4

1

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

First Second Third Fourth Fifth

Re

lativ

e H

aza

rd R

atio

Men

Women

Risk for Stroke as a Function of Pulmonary Function

P<0.01 for trend in men and P<0.05 for trend in women

FEV1 QuintileIncreasing FEV1

Hole DJ, et al. BMJ.1996;313:711-715.

1.07-2.59†

0.92-2.15

0.72-1.88

0.85-2.00

0.71-1.90

1.09-2.49

1.02-2.32

1.05-2.60

†95% CI

Reference

31

Respiratory Symptoms and Cardiovascular Mortality

1.0 1.0 1.0

1.29

1.58

1.42

1.9

2.31

1.96

0.0

0.5

1.0

1.5

2.0

2.5

Coronary Disease Stroke All Cardiovascular

Rel

ativ

e R

isk

No Respiratory Symptoms

Cough and Phlegm

Breathlessness

Rosengren A, et al. Int J Epidemiol. 1998;27:962-969.

*

*

*

*

*P<0.05 versus No Symptoms

0.99-1.66†

†95% CI

1.67-2.30

1.16-1.75

1.45-3.68

0.86-2.91

1.57-2.31

32

—

—

Arterial Stiffness in COPD Patients

11.4

8.9

0

3

6

9

12

15

COPD Patients (n=75) Control Subjects (n=42)

Aor

tic P

ulse

Wav

e V

eloc

ity(m

m/s

ec)

Sabit R, et al. Am J Respir Crit Care Med. 2007;175:1259-1265.

P<0.0001

33

Arterial Stiffness Is Independently Associated With Emphysema Severity in Patients With COPD

McAllister DA, et al. Am J Respir Crit Care Med. 2007;176:1208-1214. Permission requested.

r = 0.476

Incr

ea

sed

Art

eria

l Stif

fne

ss 12.00

Pul

se W

ave

Vel

ocity

(m

/s)

10.00

8.00

6.00

0.00 0.20 0.40 0.60

Worse Emphysema

Emphysema Severity (Pixel Index 910)

r = -0.243

Incr

ea

sed

Art

eria

l Stif

fne

ss 12.00

Pul

se W

ave

Vel

ocity

(m

/s)

10.00

8.00

6.00

25 50 75 100

FEV1 % Predicted

COPDforum is supported by

Osteoporosis

35

Osteoporosis

Disease characterised by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures of the hip, spine, and wrist

No discernable symptoms until there is a bone fracture

One out of every two women and one in four men over 50 will have an osteoporosis-related fracture in their lifetime

In the United States alone, 10 million individuals already have osteoporosis and 34 million more have low bone mass

National Institutes of Health. 2007. http://www.nih.gov/about/researchresultsforthepublic/Osteoporosis.pdf

36

Airflow Obstruction and Osteoporosis in COPD

1.93.9

6.8

11

7.610.3

20.9

33

0

5

10

15

20

25

30

35

None Mild Moderate Severe

Per

cent

of

Sub

ject

s w

ith

Ost

eopo

rosi

s

Severity of Airflow Obstruction

Men

Women

Sin DD, et al. Am J Med. 2003;114:10-14.

37

Risk Factors for Osteoporosis in COPD

Smoking

Increased alcohol intake

Low vitamin D levels

Genetic factors

Treatment with corticosteroids

Reduced skeletal muscle mass and strength

Low BMI and changes in body composition

Reduced levels of insulin-like growth factors

Chronic systemic inflammation

Ionescu AA, et al. Eur Respir J. 2003;22 (Suppl 46):64s-75s.

38

Inflammatory Mediators in Osteoporosis

IL-1

IL-6

IL-11

TNF-

Transforming growth factor (TGF) -

Nitric oxide (NO)

Receptor activator of NFB (RANK)/RANK ligand (RANKL)

Ginaldi L, et al. Immunity and Aging. 2005;2:14-18.

39

Bone Turnover and Osteoporosis are Correlated With Inflammation

NTx=N-terminal telopeptide of type I collagen, BCE=bone collagen equivalent

–0-50–0-50 0-000-00 0-500-50 1-001-00

150-50150-50

100-50100-50

50-5050-50

0-500-50

Log10 hsCRP (mg1)Log10 hsCRP (mg1)

Urin

ary

NT

x (n

M B

CE

/u)

Urin

ary

NT

x (n

M B

CE

/u)

*γ=0-288, P<0-001*γ=0-288, P<0-001

PremenopausalPostmenopausalPremenopausalPostmenopausal

0-100-10

0-000-00

–0-10–0-10

–0-20–0-20

Normal(N = 30)Normal(N = 30)

Osteoporia(N = 109)

Osteoporia(N = 109)

Osteoporosis(N = 50)

Osteoporosis(N = 50)

P for trend = 0.282P for trend = 0.282

Log 1

0 h

sCR

P (

mg1

)Lo

g 10 h

sCR

P (

mg1

)

Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women, Kim BJ, Yu YM, Kim EN, et al. Copyright © 2007 Clinical Endocrinology. Reproduced with permission of Blackwell Publishing Ltd.

40

COPD, ICS, and Osteoporotic Fracture

Severe COPD Use of ICSAdjusted Odds Ratio

for Osteoporotic Fracture

No No 1.06

No Yes 1.08

Yes No 1.47*

Yes Yes 1.48*

*P<0.05

De Vries F, et al. Eur Respir J. 2005;25:879-884.

41

Inhaled Versus Oral Corticosteroid Use and Fracture Risk in COPD

1.381.55

2.99

2.16

0

0.5

1

1.5

2

2.5

3

3.5

ICS Intermittent Continuous Any Use

Adj

uste

d O

dds

Rat

io f

or

Ver

tebr

al F

ract

ure

Systemic

*

*

McEvoy CE, et al. Am J Resp Crit Care Med. 1998;157:704-709.

*P<0.05 versus no corticosteroid

0.71-2.69†

†95% CI

1.14-4.11

1.38-6.49

0.72-3.32

COPDforum is supported by

Anaemia of Chronic Disease

43

Inflammatory Processes and Anaemia

Proinflammatorycytokines

Proinflammatorycytokines

ReactiveO2

composition

ReactiveO2

composition

ErythrocytesErythrocytes

DyserythropoiesisDyserythropoiesis

ErythrophagocytosisErythrophagocytosis

IFN-IL-1TNF

1-antitrypsin

IFN-IL-1TNF

1-antitrypsin

Shortened survival Impaired iron usage Suppressed BFU-E/CFU-E Reduced EPO-production

IFN-IL-1TNF

IFN-IL-1TNF

↓HIF-1↓HIF-1IFN-,β

IL-1TNF

IFN-,βIL-1TNF

Activated immune systemActivated immune system

MacrophagesMacrophages

TNFTNF

Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Clinical Oncology, www.nature.com/clinicalpractice/onc (Bohlius J, et al. Nat Clin Pract Oncol. 2006;3:152-164), copyright 2006.

44

Anaemia Increases Mortality Risk in Patients With COPD

Anaemia may occur in 10-15% of patients with severe COPD

Results from 2,524 COPD patients on long-term oxygen therapy showed that a low haematocrit is a strong predictor of survival in this population:

– Stronger predictor than BMI

– Associated with more hospitalisations and longer cumulative duration of hospitalisation

Similowski T, et al. Eur Respir J. 2006;27:390-396.

45

Anaemia and Mortality in COPD

262

133

0

50

100

150

200

250

300

COPD with Anaemia COPD without Anaemia

De

ath

s p

er

1,0

00

Pa

tie

nt-

yea

rs

Halpern MT, et al. Cost Effect Res Allocation. 2006;4:17-24.

P<0.001P<0.001

Metabolic Abnormalities in COPD

47

Tumor Necrosis Factor- and Diabetes

TNF- Levels Are Correlated With Insulin Resistance

IR = insulin resistance

9

8

7

6

5

4

3

2

1

0 .5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

TNF- (pg/ml)

r=0.632P<0.01

HO

MA

-R

Type 2 diabetes with IRType 2 diabetes without IRNormal

Reprinted from Res Clin Pract, Vol 52, Mishima Y, et al, Relationship between serum tumor necrosis factor-α and insulin resistance in obese men with Type 2 diabetes mellitus, pp119-123, Copyright 2001, with permission from Elsevier.

48

Reduced Pulmonary Function Associated With Diabetes Mellitus

Walter RE, et al. Am J Respir Crit Care Med. 2003;167:911-916.

——

0

1

2

3

4

Diabetes (N=280) No Diabetes (N=2,974)

Me

an

FE

V

(L)

**P<0.001 versus diabetes

1

49

Insulin Resistance Is Elevated in COPD Patients and Correlated With Inflammatory Markers

Bolton CE, et al. COPD. 2007;4:121-126.

Insulin resistance was significantly correlated With circulating TNF-α and IL-6

—

—

1.68

1.13

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

COPD (n=56) No COPD (n=29)

HO

MA

Insu

lin R

esis

tanc

e (I

U/m

L)

**P=0.032 vs no COPD

50

Prevalence of Diabetes Higher in Patients With COPD

Rana JS, et al. Diabetes Care. 2004;27:2478-2484.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

COPD (N=2,505) No COPD (N=726,840)

Per

cent

of

Sub

ject

s

*

*P<0.05 vs no COPD

51

Prevalence of Metabolic Syndrome Higher in COPD

* Metabolic syndrome 3 of the following: abdominal obesity, elevated triglycerides, reduced HDL-C, hypertension, hyperglycaemia

Marquis K, et al. J Cardiopulm Rehabil. 2005;25:226-232.

0

5

10

15

20

25

30

35

40

45

50

COPD (N=38) No COPD (N=34)

Per

cent

with

Met

abol

ic

Syn

drom

e*

COPDforum is supported by

Depression

53

Risk of Depression in Patients With COPD

1.5

2.5

1.1 1

0

0.5

1

1.5

2

2.5

3

All Patients (N=162) FEV <50% Predicted (N=60)

FEV 50-80% (N=102)

Controls

Rel

ativ

e R

isk

for

Dep

ress

ion

(0.8-2.6)

(1.2-5.4)

(0.5-2.1)

van Manen JG, et al. Thorax. 2002;57:412-416.

1 1

Reference

54

Variables Associated With Depression and Anxiety in Patients With COPD

Physical disability

Long-term oxygen therapy

Low body mass index

Severe dyspnoea

FEV1 <50% predicted

Poor quality of life

Presence of cormorbidity

Living alone

Female gender

Current smoking

Low social class status

Maurer J, et al. Chest. 2008;134 (4 Suppl):43S-56S.Maurer J, et al. Chest. 2008;134 (4 Suppl):43S-56S.

COPDforum is supported by

Gastrointestinal Disease

56

Helicobacter pylori and Inflammatory Mediators in Gastric Disease

HP-NAP VacANH3

IL-8

Neutrophil<Activation>

Monocyte

<Adhesion>CD11/CD18CD11/CD18

ICAM-1 VCAM-1

<Chemotaxis>

ROSMonochloramineProtease IL-1

TNF-αTissue factorPAI-2

IL-1TNF-α

0 CagA0 CagA

00

ICAM-1ICAM-1

Reprinted from Free Radical Biol Med, Vol 33, Naito Y, et al, Molecular and cellular mechanisms involved in Helicobacte pylori-induced inflammation and oxidative stress, pp 323-336, Copyright 2002, with permission from Elsevier.

57

Increased Prevalence of Esophagitis, Gastritis, or Gastric Ulcers in Patients With COPD

32

17

0

5

10

15

20

25

30

35

COPD Controls

Per

cent

of

Pat

ient

s w

ith G

astr

ic

Dis

ease

Mapel DW, et al. Chest. 2000;117:346-353.

*

*P<0.05 versus controls

58

6.4

4.7

3.5

0

1

2

3

4

5

6

7

Non-malignant GI Malignant GI COPD

SM

RIncreased Risk for COPD Mortality in Patients With Crohn’s Disease

692 patients followed for 14 years Standardised mortality ratios (SMRs, observed/expected deaths) were

calculated

Jess T, et al. Gut. 2006;55:1248-1254.

*

*

*

* P<0.05 versus expected, GI=gastrointestinal3.2-11.5† †95% CI

1.3-7.5

1.7-10.2

Effects of COPD Treatment on Systemic Comorbidities

60

Effects of Tiotropium on Inflammatory Markers in COPD Patients

Areas Under the Curve for IL-6, IL-8, and MPO

*P=0.034, †P=0.043,‡P=0.079 versus placebo

Reproduced with the permission of European Respiratory Society Jounrals Limited. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Powrie DJ, et al. Eur Resp J. 2007;30:472-478.

3.8

3.7

3.6

3.5

Placebo Tiotropium

IL-6

lo

g10

we

ek

•pg

•mL

-1

*

15

14

13

11

Placebo Tiotropium

IL-8

we

ek

•pg

•mL

-1 x

104

3.25

3.20

3.15

3.05

Placebo Tiotropium

†

12 3.10

‡

MP

O l

og

10 w

ee

k•IU

•mL

-1

61

-0.145

-0.2-0.168

0.1

0.2

0.074

Changes From Baseline in CRP and IL-6 With Fluticasone and Fluticasone/Salmeterol

Sin DD, et al. Am J Resp Crit Care Med. 2008; 177:1207-1214.

No Changes from Baseline Were Statistically Significant

CRP mg/L) IL-6 (pg/mL)-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

0.2

0.25

Ch

ang

e fr

om

Bas

elin

e

Placebo (n=39)

Fluticasone (n=85)

Fluticasone/Salmeterol (n=88)

-1.923-1.732†

†95% CI

-0.5-1.1

-0.6-0.9

-1.205-2.674

-1.3-0.5

-1.385-0.691

62

Systemic Comorbiditites in COPD

Skeletal Muscle Dysfunction

Cardiovascular

–CHF

–Arrhythmias

–Hypertension (systemic pulmonary)

Osteoporosis

Anaemia of Chronic Disease

Metabolic Disease

– Diabetes

– Metabolic Syndrome

Depression

Gastrointestinal

–Ulcer Disease

COPD is a Systemic DiseaseCOPD is a Systemic Disease

Agusti AG, et al. Eur Respir J. 2003;21:347-360.Sevenoaks MJ, Stockley RA. Respir Res. 2006;7:70-78.

Chatila et al. Proc Am Thorac Soc. 2008;5:549-555.Luppi et al. Proc Am Throrac Soc. 2008;5:848-856.

63

Systemic Comorbiditites in COPD

Cardiovascular

–CHF

–Arrhythmias

–Hypertension (systemic pulmonary)

Metabolic

–Diabetes

Orthopedic

–Osteoporosis

Gastrointestinal

–Ulcer Disease

Haematologic

–Malignancies

–Anaemia

Psychiatric

–Depression

Ophthalmologic

COPD is a Systemic DiseaseCOPD is a Systemic Disease

Agusti AG, et al. Eur Respir J. 2003;21:347-360.Sevenoaks MJ, Stockley RA. Respir Res. 2006;7:70-78.

Chatila et al. Proc Am Thorac Soc. 2008;5:549-555.Luppi et al. Proc Am Throrac Soc. 2008;5:848-856.

64

Assessing Comorbidities in COPD

Agusti A and Jardim J, personal communication.

Look forLook for

Look forLook for

COPDCOPD ComorbiditiesComorbidities

If SmokerIf Smoker