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Pulmonary
Arterial
Hypertension
(PAH)
and PAH in
Systemic
Sclerosis (SSc)
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Contents
Title
Slide
PAH Explained
What is PAH?
6
Histopathology
7
Definition
8
NYHA/WHO Classification
9
WHO classification
10
How common is it?
12
Why does it develop?
13
What are the symptoms?
16
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Contents
Title
Slide
Diagnosing & Assessing PAH
Early diagnosis is crucial
18
How is it diagnosed?
19
Why can it be difficult to diagnose?
20
Screening high risk populations
21
Echocardiography
23
Right heart catheterisation
25
Assessing PAH: 6-minute walk test
Treating PAH
28
How is it treated?
30
3
Contents
Title
Slide
PAH-SSc Explained
PAH in Systemic Sclerosis
34
What is Systemic Sclerosis?
35
What is PAH-SSc?
39
How common is PAH-SSc?
40
What is the life expectancy in PAH-SSc?
41
What are the symptoms of PAH-SSc?
42
Further information
Actelion contact details
45
4
PAH
Explained
5
What is PAH?
• PAH is a syndrome characterised by a progressive increase in pulmonary
vascular resistance (PVR)
• leads to right ventricular overload
• eventually leads to right ventricular failure and premature death1
• If untreated, the median survival is 2.8 years2 which is comparable with some
malignancies
• Increased PVR is related to progressive changes in the pulmonary
arterioles
•
•
•
•
vasoconstriction
obstructive remodelling of the pulmonary vessel wall
inflammation
in-situ thrombosis
1. Sitbon O et al. Circulation 2005
2. D’Alonzo GE et al. Ann Intern Med 1991
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PAH: histopathology
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PAH: definition
• Sustained elevation of mean pulmonary arterial pressure (mPAP)1
• >25mmHg at rest
• >30mmHg while exercising
• Normal pulmonary capillary wedge pressure
• 15mmHg
• Earliest symptom is often dyspnoea on physical exertion
• Other symptoms may include2,3
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•
•
•
•
syncope or near syncope
fatigue
peripheral oedema
chest tightness
chest pain on physical exertion
1. Galie N et al. Eur Heart J 2004.
2. Gaine SP et al. Lancet 1998
3. Barst RJ et al. J Am Coll Cardiol 2004
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PAH: classification1
1.
PAH
2.
• Idiopathic PAH
• Familial PAH
• Associated with:
PH associated with left heart
disease
3.
PH associated with respiratory
disease
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•
•
•
•
•
•
•
•
Connective tissue disease
CHD (shunts)
Portal hypertension
HIV infection
Sickle cell disease
Drugs and toxins
Other
Associated with significant venous or
capillary involvement
Persistent pulmonary hypertension of
the newborn
1. Simonneau G et al. JACC 2004
•
•
COPD
Interstitial lung diseases
4.
PH due to chronic thrombotic
and/or embolic disease
5.
Miscellaneous
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PAH: how is severity classified?
• Classified according to a functional class system1
• New York Heart Association (NYHA)/ World Health Organisation (WHO)
• There are four WHO functional classes (WHO FC)1
• WHO FC I being the least severe
• WHO FC IV being the most advanced
• different classes reflect the impact on a patient’s life in terms of physical
activity and symptoms
(see next slide for WHO classification table)
1. Barst RJ et al. J Am Coll Cardiol 2004
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WHO Functional Class1
WHO FC
Symptomatic profile
Class I
Patients with pulmonary hypertension but without resulting limitation of physical
activity. Ordinary physical activity does not cause dyspnoea or fatigue, chest
pain or near syncope
Class II
Patients with pulmonary hypertension resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity causes undue
dyspnoea or fatigue, chest pain or near syncope
Class III
Patients with pulmonary hypertension resulting in marked limitation of physical
activity. They are comfortable at rest. Less than ordinary activity causes undue
dyspnoea or fatigue, chest pain or near syncope
Class IV
Patients with pulmonary hypertension with inability to carry out any physical
activity without symptoms. These patients manifest signs of right heart failure.
Dyspnoea and/or fatigue may even be present at rest
1. Barst RJ et al. J Am Coll Cardiol 2004
11
PAH: how common is it?
• PAH is rare
• an estimated prevalence of 3050 cases per million1
• most common in young women
• Mean age of diagnosis 36 years2
• The prevalence in certain at-risk groups is higher
• HIV-infected patients (0.50%)3
• sickle cell disease (2040%)4
• systemic sclerosis (16%)5
• True prevalence may be higher
1.
2.
3.
4.
5.
Peacock AJ. BMJ 2003
Gaine SP et al. Lancet 1998
Sitbon O et al. Am J Resp Crit Care Med 2008
Lin EE et al. Curr Hematol Rep 2005
McGoon M et al. Chest 2004
12
PAH: why does it develop?
• Exact cause of PAH remains unknown
• Endothelial dysfunction occurs early on in the disease process
• Endothelial dysfunction results in
•
•
•
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reduced production of vasodilators
over production of vasoconstrictors
endothelial and smooth muscle cell proliferation
remodelling of the pulmonary vascular bed and increased vascular resistance
13
PAH: why does it develop?
• Reduced production of vasodilators
• Prostacyclin
• potent vasodilator
• potent inhibitor of platelet activation
• therapy with synthetic forms of prostacyclin may help to correct this deficiency
• Nitric oxide
• potent vasodilator
• possesses anti-proliferative properties
• vasodilatory effect is mediated by cGMP
• rapidly degraded by phosphodiesterases
14
PAH: why does it develop?
• Increased production of vasoactive compounds
• Endothelin (ET)
• elevated levels are seen in PAH patients13
• levels correlate with disease severity4
• deleterious effects mediated through ETA and ETB receptors5
• fibrosis
• hypertrophy and cell proliferation
• inflammation
• vasoconstriction
• endothelin receptor antagonists can block these effects
• ET, nitric oxide and prostacyclin have been the principal focus of
research into treatments for PAH
1.
2.
3.
4.
5.
Stewart DJ et al. Ann Inter Med 1991
Vancheeswaran R et al. J Rheum 1994
Yoshibayashi M et al. Circulation 1991
Galiè N et al. Eur J Clin Invest 1996
Channick RN et al. Lancet 2001
15
PAH: what are the symptoms?
• High resistance to blood flow through the lungs causes right heart
dysfunction and produces:1,2
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dyspnoea
fatigue
dizziness
syncope
peripheral oedema
chest pain, particularly during physical exercise
• Symptoms are non-specific and are commonly attributed to other
conditions
• Over time, symptoms become more severe and limit normal daily
activities
1. Gaine SP et al. Lancet 1998
2. Barst RJ et al. J Am Coll Cardiol 2004
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Diagnosing &
Assessing
PAH
17
PAH: Early diagnosis is crucial
• If untreated, the median survival is 2.8 years which is comparable with
some malignancies1-3
• diagnosis can be delayed for months or years and frequently occurs when
disease is relatively advanced4
• mean time from onset to diagnosis is estimated to be approximately 2 years5
• Although patients progress at different rates; early stage PAH is still a
devastating condition and can rapidly deteriorate
• Early diagnosis and intervention is therefore crucial
• patients who begin targeted therapy in less severe PAH (WHO FCI/II)
demonstrate a better prognosis than those in a more severe stage (WHO
FCIII/IV)6
1.
2.
3.
4.
5.
6.
D'Alonzo GE et al. Ann Intern Med 1991
Kato I et al. Cancer 2001
Bjoraker JA et al. Am J Respir Crit Care Med 1998
Gaine SP et al. Lancet 1998
Humbert M et al. Am J Respir Crit Care Med 2006
Sitbon O et al. J Am Coll Cardiol 2002
18
PAH: How is it diagnosed?
•
Diagnosis requires a series of investigations in a four-stage approach:1
i.
ii.
iii.
iv.
Clinical suspicion of pulmonary hypertension
• symptoms, screening and incidental findings
Detection of pulmonary hypertension
• ECG, chest radiograph, Doppler echocardiography
Identification of other causes of pulmonary hypertension
• pulmonary function test, blood gas samples, HRCT
PAH evaluation and classification
• functional capacity and haemodynamics
1. Galie N et al. Eur Heart J 2004
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PAH: Why can it be difficult to
diagnose?
• Low awareness/not a condition seen every day by general physicians
• It often comes in disguise:
• Non-specific symptoms that are often mild and common to other conditions
• Confusion with other diseases such as asthma, COPD and other
cardiovascular disorders
• Patients typically see many health professionals before diagnosis
• No simple means of excluding PAH
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PAH: Screening high risk populations
• Key to early diagnosis – screening high risk populations:
– Family members of a patient with familial Pulmonary Arterial
Hypertension (FPAH)
– Patients with systemic sclerosis (SSc)
– Patients with HIV
– Patients with portopulmonary hypertension (PoPH)
• International guidelines recommend annual screening with
Doppler echocardiography.1-3
• Right heart catheterisation still only method for definitive
diagnosis
1.
2.
3.
Hachulla E et al Ann Rheum Dis 2004
Galie N et al. Eur Heart J 2004
McGoon M et al. Chest 2004
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PAH: Screening high risk populations
• Results of a disease registry in France:
– without screening, the majority of patients were diagnosed in WHO FC III
or FC IV, and only 24% of patients were in WHO FC II at diagnosis.1
1
1.
2.
Humbert M et al. Am.J.Respir.Crit Care Med 2006
Hachulla E et al. Arthritis Rheum 2005
2
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Echocardiography
23
Echocardiography:
its value as a screening tool
24
Right heart catheterisation:
the diagnostic gold standard
25
Right heart catheterisation:
the diagnostic gold standard
• RHC should always assess
•
•
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•
•
right atrial pressure (RAP)
systolic, diastolic and mean pulmonary arterial pressure (PAP)
pulmonary capillary wedge pressure (PCWP)
cardiac output / index
PVR and systemic vascular resistance
blood pressure and arterial and mixed venous oxygen saturation
• RHC can assess vasoreactive response
• shown in only 1015% of patients1
• sustained response is shown in less than 7% of patients1
1. Sitbon O et al. Circulation 2005
26
Right heart catheterisation:
the diagnostic gold standard
27
Assessing PAH: 6-minute walk test
• The 6-minute walk test (6MWT) is an evaluation of exercise capacity in
patients with PAH
• The 6-MWT is a critical endpoint in clinical studies assessing therapeutic
options
• The 6-MWT should be performed under supervision and according to a
standardised protocol1
1. ATS. Am J Crit Care Med 2002
28
Treating
PAH
29
29
PAH: how is it treated?
• There is currently no cure for PAH
• Prognosis is influenced by the status of WHO FC when treatment is
started – those who start therapy in WHO FC I or II demonstrate a better
prognosis than those whose therapy is started in the more severe stages1
• By recognising and treating patients as early as possible, disease
progression may be delayed
• Without treatment, patients in WHO FC II can rapidly deteriorate within 6
months to more advanced PAH as evidenced by progression of
symptoms.2
1.
Sitbon O et al. J Am Coll Cardiol 2002
2.
Galiè N et al. Lancet 2008
30
PAH: how is it treated?
• Treatment options have progressed considerably in the last decade
• The main medical treatment options are:1
• Treatments that are routinely used but with little evidence of impact on the
disease progression
• anticoagulants – to address the observed thrombotic changes and potential
predisposition in the pulmonary microcirculation for in-situ thrombosis
• diuretics – for treatment of right heart failure
• oxygen therapy – to maintain oxygen saturation at >90% at all times
• calcium channel blockers – less than 10% of IPAH patients benefit from CCB
therapy. If not used in appropriate candidates CCBs may be deleterious2
1. Humbert H et al. N Engl J Med 2004
2. Sitbon O et al. Circulation 2005
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PAH: how is it treated?
• Treatments that have been specifically studied in PAH
• endothelin receptor antagonists - endothelin is implicated in the pathogenesis of
PAH. Endothelin is found to be elevated in patients with PAH and are directly
related to disease severity and prognosis. Endothelin receptor antagonists block
the ETA receptor alone or both the ETA and ETB receptors1,2
• prostacyclin analogues – may be delivered by continuous intravenous or
subcutaneous infusion or via an intermittent nebuliser3
• phosphodiesterase 5 inhibitors – oral agents which induce relaxation and
antiproliferative effects on vascular smooth muscle cells4
• In severe cases surgical options may be considered
1.
2.
3.
4.
Channick RN et al. Lancet 2001
Galie N et al. Eur Heart J 2004
Humbert H et al. N Engl J Med 2004
Galiè N et al. N Engl J Med 2005
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PAH-SSc
Explained
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PAH in Systemic Sclerosis
• Systemic sclerosis (SSc); also known as scleroderma
• Pulmonary Arterial Hypertension (PAH) occurs in approximately one in
seven scleroderma patients1
• Pulmonary complications, namely PAH and pulmonary fibrosis, are a
common cause of death in SSc patients2
• Symptoms such as breathlessness, fatigue on exercise and syncope are
common to other respiratory or cardiac complaints3,4
• PAH should be considered in the daily management of SSc patients and
screening is the key to establishing early diagnosis
• International guidelines recommend screening by Doppler
echocardiography annually and/or in the presence of unexplained
breathlessness5
1.
2.
3.
4.
5.
Hachulla E et al. Ann Rheum Dis 2004
Steen V et al. Ann Rheum Dis 2007
Runo JR et al. Lancet 2003
McGoon M et al. Chest 2004
Galiè et al. Eur Heart J 2004
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What is Systemic Sclerosis?
• Chronic autoimmune connective tissue disease characterised by
excessive collagen deposition in the skin and internal organs such as the
gastrointestinal tract, kidney, heart and lung1,2
• Symptoms may be caused by vascular dysfunction, inflammation and
progressive fibrosis which lead to occlusion of the microvasculature
1. Mouthon L et al. Eur Respir J 2005
2. Denton CP et al. Trends Immunol 2005
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What is Systemic Sclerosis?
• SSc is commonly divided into two major subsets reflecting the pattern of
tissues and organs affected, autoantibody specificities and clinical
findings:
• Limited – LcSSc is defined by skin thickening in areas solely distal to the
elbows and knees, with or without facial effects, such as telangiectases
• Diffuse – DcSSc is defined by the presence of skin thickening that is
proximal, as well as distal, to the elbows and knees, with or without facial or
truncal effects
• On the base of diffuse fibrotic involvement, disease is frequently more
severe in patients with DcSSc
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What is Systemic Sclerosis?
• Pathogenesis of SSc is complex and, as yet, not completely understood
• SSc does have three cardinal features:
– Vasculopathy (damage to and remodelling of the blood vessels)
– inflammation/autoimmune activation
– fibrosis (formation or development of excess fibrous connective
tissue)
• Vascular dysfunction appears to be an early event in the pathophysiology
of SSc and is central to the serious complications of SSc
• The underlying vascular dysfunction is shared by several of the
manifestations of SSc, including PAH, scleroderma renal crisis and, the
most visible manifestation, digital ulceration
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What is Systemic Sclerosis?
The nature of the vascular dysfunction in SSc:
38
What is PAH-SSc?
• PAH can be idiopathic (iPAH) or can be associated with a number of
conditions (Associated Pulmonary Arterial Hypertension - APAH)
• Associated conditions include HIV infection, congenital heart disease,
sickle cell disease and connective tissues diseases, such as SSc and
Systemic Lupus Erythematosus (SLE)
39
How common is PAH-SSc?
• The overall prevalence of all types of PAH is an estimated 30-50 cases
per million1
• The prevalence of PAH in certain at-risk groups is substantially higher
and a mean of 16% of patients with systemic sclerosis are thought to go
on to develop PAH2
• For information on why PAH-SSc develops, refer to slide 13
1. Peacock AJ. BMJ 2003
2. McGoon M et al. Chest 2004
40
What is the life expectancy in
PAH-SSc?
• In SSc patients, pulmonary complications, such as PAH and interstitial
lung disease, are now the leading causes of death1
• Patients with PAH-SSc have a particularly poor prognosis compared to
those with SSc without PAH2
• PAH-SSc patients have a poor prognosis compared with iPAH patients,
with a mortality rate three times as high3
1. Steen V et al. Ann Rheum Dis 2007
2. Koh ET et al. Br J Rheumatol 1996
3. Kawut SM et al. Chest 2003
41
What are the symptoms of
PAH-SSc?
• The symptoms of PAH-SSc are essentially the same as those of iPAH
• In SSc patients, an in-depth review of the patient's medical history is
required. Reduced daily activities and exercise breathlessness may not
always be the first symptom reported by patients
• Some SSc patients have already reduced their daily activities due to
mobility problems (i.e. skin involvement and joint problems) and / or the
fact that they are often older than iPAH patients
42
How is PAH-SSc diagnosed and
treated?
• Refer to slide 18 for information on how PAH-SSc is diagnosed
• Refer to slide 30 for information on how PAH-SSc is treated
43
Further
Information
44
Contacts
For further information visit www.pah-info.com
©2008 Actelion Pharmaceuticals Ltd.
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CH-4123 Allschwil
Switzerland
www.actelion.com
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