Download Slide 1

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
Classification
9
How common is it?
10
Why does it develop?
11
What are the symptoms?
14
Diagnosing PAH
How is it diagnosed?
16
Why can it be difficult to diagnose?
17
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Contents
Title
Slide
PAH diagnostic approach
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Echocardiography
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Right heart catheterisation
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Assessing PAH
6-minute walk test
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How is severity classified?
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NYHA/WHO classification
Treating PAH
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How is it treated?
29
PAH-SSc Explained
PAH in Systemic Sclerosis
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What is Systemic Sclerosis?
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Contents
Title
Slide
What is PAH-SSc?
37
How common is PAH-SSc?
38
What is the life expectancy in PAH-SSc?
39
What are the symptoms of PAH-SSc?
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Further information
Actelion contact details
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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
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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 include1,2
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syncope or near syncope
fatigue
peripheral oedema
chest tightness
chest pain on physical exertion
1. Gaine SP et al. Lancet 1998
2. 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
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•
COPD
Interstitial lung diseases
4.
PH due to chronic thrombotic
and/or embolic disease
5.
Miscellaneous
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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 (0.46%)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 et al. Am J Resp Crit Care Med 2008
Lin EE et al. Curr Hematol Rep 2005
McGoon M et al. Chest 2004
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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
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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
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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
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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
PAH
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PAH: how is it diagnosed?
• Early symptoms of PAH are often mild and common to other conditions
• diagnosis can be delayed for months or years1
• diagnosis frequently occurs when disease is relatively advanced1
• diagnosis is made only after other conditions have been ruled out
• Diagnosis requires a series of investigations in a four-stage approach
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clinical suspicion
detection of PAH
identification of other causes of PAH
evaluation and classification
1. Gaine SP et al. Lancet 1998
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PAH diagnostic approach
Pulmonary hypertension diagnostic approach. ABG: arterial blood gases, CT: computerised
tomography; PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; TT: transthoracic;
VO2: oxygen consumption; Cath: catheterisation.
1. ESC Guidelines. European Heart Journal 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
• Confusion with other diseases such as asthma and other cardiovascular
disorders
• Patients typically see many health professionals before diagnosis
• No simple means of excluding PAH
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Echocardiography
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Echocardiography:
its value as a screening tool
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Right heart catheterisation:
the diagnostic gold standard
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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
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Right heart catheterisation:
the diagnostic gold standard
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Assessing
PAH
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6-minute walk test (6MWT):
evaluation of exercise capacity
• The 6-MWT is reflective of activities of daily living1
• 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 protocol2
1. Solway S et al. Chest 2001
2. ATS. Am J Crit Care 2002
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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 functional classes1
• class I being the least severe
• class IV being the most advanced
• Different classes reflect the impact on a patient’s life in terms of physical
activity and symptoms
1. Barst RJ et al. J Am Coll Cardiol 2004
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WHO classification1
Class
Symptomatic profile
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
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
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
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
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Treating
PAH
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PAH: how is it treated?
• There is currently no cure for PAH
• The main 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
ESC Guidelines. European Heart Journal 2004
Sitbon et al. Thorax 2005
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
1
seven scleroderma patients
• 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:
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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)
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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 connective tissue disease are
thought to go on to develop PAH2
• For information on why PAH-SSc develops, refer to slide 11
1. Peacock AJ. BMJ 2003
2. McGoon M et al. Chest 2004
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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
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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
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How is PAH-SSc diagnosed and
treated?
• Refer to slide 16 for information on how PAH-SSc is diagnosed
• Refer to slide 29 for information on how PAH-SSc is treated
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Further
Information
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Contents
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