This slide set has been developed by Actelion Pharmaceuticals Ltd as an
educational resource for healthcare providers and other interested parties
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Pulmonary Arterial Hypertension (PAH)
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Contents
Title
Slide
PAH explained
What is PAH?
9
Changes in the pulmonary arteries in PAH
10
Classification of PH
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How common is PAH?
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Why does PAH develop?
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The role of Endothelin
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The role of Prostacyclin
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The role of Nitric oxide
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What are the symptoms of PAH?
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Contents
Title
Slide
Diagnosing PAH
How is PAH diagnosed?
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Clinical practice guidelines for the diagnosis of PAH
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Four stage approach to diagnosis
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Echocardiography – value as a screening tool
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Right heart catheterisation – the diagnostic gold standard
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Screening for PAH
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The value of screening
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Contents
Title
Slide
Treating PAH
How is PAH treated?
32
General measures and supportive therapy
33
Advanced (PAH-specific) therapy
34
Surgical intervention
35
Treatment guidelines: Goal-oriented therapy
36
The importance of early identification and intervention in PAH
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Contents
Title
Slide
Assessing the patient
Assessing the severity of PAH
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Functional class
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Functional class and survival
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6 minute walk test
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Cardiopulmonary exercise testing
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Haemodynamic parameters
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Biochemical markers
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Contents
Title
Slide
PAH-SSc explained
PAH in Systemic Sclerosis
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How is PAH-SSc detected?
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Screening for PAH in SSc
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How is PAH-SSc treated?
Further information
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Actelion contact details
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PAH explained
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What is PAH?
• Progressive disease caused by narrowing or
tightening of the pulmonary arteries
• Right side of the heart becomes enlarged due to the
increased strain of pumping blood through the lungs
• Strain leads to the common symptoms of PAH
(breathlessness, fatigue, weakness, angina
and syncope)1
• PAH is characterised by;1,2
– mean PAP ≥ 25mmHg at rest
– mean PCWP ≤ 15mmHg
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1. Galiè N et al. Eur Heart J 2009; 2. Badesch DB et al. J Am Coll Cardiol 2009
Changes in the pulmonary arteries in PAH
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Classification of PH
Group 1. Pulmonary arterial hypertension (PAH)
• Idiopathic (IPAH)
• Heritable (HPAH)
– bone morphogenetic protein receptor type 2 (BMPR2)
– activin receptor-like kinase 1 gene (ALK1), endoglin
(with or without haemorrhagic telangiectasia)
– unknown
• Drug- and toxin-induced
• Associated with (APAH):
–
–
–
–
–
–
connective tissue diseases
Human immunodeficiency virus (HIV) infection
portal hypertension
congenital heart disease (CHD)
schistosomiasis
chronic haemolytic anaemia
• Persistent pulmonary hypertension of the newborn
(PPHN)
Group 1’. Pulmonary veno-occlusive disease (PVOD) and/or
pulmonary capillary haemangiomatosis (PCH)
Group 2. Pulmonary hypertension due to left heart disease
• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease
Group 3. Pulmonary hypertension due to lung
diseases and/or hypoxemia
• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease (ILD)
• Other pulmonary diseases with mixed restrictive
and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities
Group 4. Chronic thromboembolic pulmonary
hypertension (CTEPH)
Group 5. PH with unclear multifactorial
mechanisms
• Haematological disorders: myeloproliferative
disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary
Langerhans cell histiocytosis,
lymphangioleiomyomatosis, neurofibromatosis,
vasculitis
• Metabolic disorders: glycogen storage disease,
Gaucher disease, thyroid disorders
• Others: tumoural obstruction, fibrosing
mediastinitis, chronic renal failure on dialysis
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Simonneau G et al. J Am Coll Cardiol 2009
Classification of PH
• Idiopathic PAH (IPAH)
– sporadic disease in which there is neither a family history
of PAH nor an identified risk factor1
• Heritable PAH (HPAH)
– accounts for at least 6% of cases of PAH2
– associated with mutations in the bone morphogenetic
protein receptor 2 (BMPR2)3
• Drug and toxin-induced
– rare side effect of certain anorexigenic agents, such
as fenfluramine1,4
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Lane KB et al. Nat Genet 2000;
3. Morrell NW. F1000 Biol Rep 2010; 4. Galiè N et al. Eur Heart J 2009
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Classification of PH
• Associated PAH (APAH):1
PAH associated with connective tissue disease
Well-recognised complication of connective tissue diseases,
such as systemic sclerosis (SSc) and systemic lupus
erythematosus (SLE)
PAH associated with HIV infection
Relatively rare but well documented complication.
Long-term conditions such as PAH increasingly responsible
for HIV-associated morbidity and poor prognosis2,3
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Sitbon O. AIDS 2008; 3. Kanmogne GD. Curr Opin Pulm Med 2005
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Classification of PH (cont.)
• Associated PAH (APAH):1
PAH associated with portal hypertension
Well-recognised complication of chronic liver diseases
resulting from portal hypertension (portopulmonary
hypertension)
PAH associated with congenital heart disease
Can arise in patients with a variety of congenital shunts
and can persist following corrective surgery. Eisenmenger's
syndrome most severe form1,2
PAH associated with schistosomiasis
PAH associated with sickle cell disease
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Diller GP et al. European Heart Journal Supplements 2007
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How common is PAH?
• PAH is rare
– estimated prevalence of 15–50 cases per million1
• IPAH
– annual incidence of 1–2 cases per million people in the
US and Europe2,3
– 2-4 times as common in women as men2,3
• Prevalence is higher in at risk groups:
–
–
–
–
systemic sclerosis (~7–12%)4,5
HIV infection (0.5%)6
sickle cell disease (2–3.75%)7,8
schistosomiasis (4.6%)9
1.Peacock AJ et al. Eur Respir J 2007; 2. Gaine SP, Rubin LJ. Lancet 1998; 3. Badesch DB et al. Chest 2010; 4. Hachulla E et al.
Arthritis Rheum 2005; 5. Mukerjee D et al. Ann Rheum Dis 2003; 6. Sitbon O et al. Am J Respir Crit Care Med 2008;
7. Machado RF, Gladwin MT. Chest 2010; 8.Fonseca GH, et al. Eur Respir J 2011; 9. Lapa M et al. Circulation 2009
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Why does PAH develop?
• Exact causes unknown
• Complex, multi-factorial condition1,2
• Endothelial dysfunction occurs early in disease
pathogenesis and leads to1:
–
–
–
–
endothelial and smooth muscle proliferation
remodelling of the vessel wall
impaired production of vasodilators (NO, prostacyclin)
overexpression of vasoconstrictors (endothelin-1)
1. Galiè N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30:
2493–537.
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2. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension:
2009;119:2250–94.
The role of endothelin
• Endothelin-1 (ET-1)
– 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 effects6
1. Stewart DJ et al. Ann Inter Med 1991; 2. Vancheeswaran R et al. J Rheum 1994;
3. Yoshibayashi M et al. Circulation 1991; 4. Galiè N et al. Eur J Clin Invest 1996;
5. Humbert M et al. N Engl J Med 2004; 6. Channick RN et al. Lancet 2001
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The role of prostacyclin
• Prostacyclin1,2
–
–
–
–
potent vasodilator
inhibitor of platelet activation
low levels in patients with PAH
therapy with prostacyclin or prostacyclin analogues can
help to correct this deficiency
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1. Humbert M et al. N Engl J Med 2004; 2. McGoon MD, Kane GC. Mayo Clin Proc 2009;84:191–207
The role of nitric oxide
• Nitric oxide1,2
–
–
–
–
–
–
potent vasodilator
possesses anti-proliferative properties
impaired production in PAH3
vasodilatory effect is mediated by cGMP
rapidly degraded by phosphodiesterases (PDEs)
therapy with oral PDE-5 inhibitors reduces degradation4
1. Galiè N et al. Prog Cardiov Dis 2003; 2. Humbert M et al. N Engl J Med 2004;
3. McLaughlin VV et al. Circulation 2009; 4. Galiè N et al. N Engl J Med 2005
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What are the symptoms of PAH?
• High resistance to blood flow through the lungs
causes right heart dysfunction, decreased cardiac
output and produces:1–3
–
–
–
–
–
–
dyspnoea
fatigue
dizziness
syncope
peripheral oedema
chest pain, particularly during physical exercise
1. Galiè N et al. Eur Heart J 2009; 2. Gaine SP et al. Lancet 1998;
3. Barst RJ et al. J Am Coll Cardiol 2004
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What are the symptoms of PAH?
• Early symptoms mild and non-specific
• Commonly attributed to other conditions
• Over time, symptoms become more severe and limit
normal daily activities
• Delayed diagnosis common:
– symptom onset to disease diagnosis > 2 years1,2,3
– frequently not recognised until the disease is relatively
advanced1,3
1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Badesch DB et al. Chest 2010;
3. Gaine SP, Rubin LJ. Lancet 1998
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Diagnosing PAH
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How is PAH diagnosed?
• PAH is a challenging disease to diagnose accurately;
diagnosis cannot be made on symptoms alone
• Series of investigations to:1,2
– determine whether there is a likelihood of PAH being
present
– confirm the diagnosis based on initial non-invasive testing
– clarify the specific aetiology
– evaluate the functional and haemodynamic impairment of
the individual patient
– determine an appropriate treatment category
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1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009
Clinical practice guidelines for the diagnosis of
PAH
ESC/ERS clinical guidelines for the
diagnosis of PAH1
Adapted with permission of Oxford University Press, from Guidelines for the diagnosis
and treatment of pulmonary hypertension, Galiè N, Hoeper MM, Humbert H, et al. Eur
Heart J 2009;30:2493–537 Copyright © 2009, permission conveyed through Copyright
Clearance Center, Inc.
ACCF/AHA Diagnostic Approach to PAH2
Adapted with permission of Wolters Kluwer Health, from ACCF/AHA. ACCF/AHA 2009
expert consensus document on pulmonary hypertension: a report of the American
College of Cardiology Foundation Task Force on Expert Consensus Documents and the
American Heart Association: developed in collaboration with the American College of
Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension
Association, McLaughlin VV, Archer SL, Badesch DB, et al. Circulation 119:2250–94
Copyright © 2009, permission conveyed through Copyright Clearance Center, Inc.
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1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009
Four stage approach to diagnosis
• Clinical suspicion of PAH
– symptoms, known risk factors
• Exclusion of Group 2 (left heart disease) and Group 3 (lung
disease) PH
– ECG, chest radiograph, echocardiography, PFTs, HRCT
• Exclusion of Group 4 (CTEPH) PH
– ventilation/perfusion lung scan
• PAH evaluation and characterisation
– CT pulmonary angiography, CMRI, haematology, biochemistry,
serology, and ultrasonography
– functional class and exercise capacity
– allright
heart
catheterisation
Note: Not
tests may
be performed
at all centres (RHC)
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Galiè N et al. Eur Heart J 2009
Echocardiography – value as a screening tool
26
Right heart catheterisation – the diagnostic gold
standard1
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1. Galiè N et al. Eur Heart J 2009
Right heart catheterisation – the diagnostic gold
standard
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Screening for PAH
• Improving early diagnosis – screening high
risk populations:
–
–
–
–
–
family members of a patient with heritable PAH (HPAH)
patients with systemic sclerosis (SSc)
patients with HIV
patients with portopulmonary hypertension (PoPH)
patients with congenital heart disease
• European and US guidelines recommend annual
screening with Doppler echocardiography1,2
• Right heart catheterisation required for definitive
diagnosis
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1. Galiè N et al. Eur Heart J 2009; 2. McGoon M et al. Chest 2004
The value of screening
• 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 diagnosis1
– with screening, PAH was detected at an earlier stage2
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1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Hachulla E et al. Arthritis Rheum 2005
Treating PAH
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How is PAH treated?
• Currently no cure for PAH
• Modern advanced PAH therapies can markedly
improve a patient’s symptoms and slow the rate of
clinical deterioration1,2
• Management is complex, involving use of a range of
treatment options:
–
–
–
–
general measures
conventional or supportive therapy
advanced therapy (PAH-specific therapy)
surgical intervention
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1. Galiè N et al. Eur Heart J 2009; 2. Humbert M et al. Circulation 2010
General measures and supportive therapy
• General measures1–3
– limit effects of external circumstances
• avoid pregnancy
• prevention and prompt treatment of chest infections
• awareness of the potential effects of altitude
• Conventional or supportive therapy1–3
– provide symptomatic benefit
•
•
•
•
supplemental oxygen
oral anticoagulants
diuretics
CCBs
1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009;
3. Badesch DB et al. Chest 2004
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Advanced (PAH-specific) therapy
• Endothelin receptor antagonists (ERAs)
– oral treatments that act by blocking the binding of ET to
either one (single antagonist) or both (dual antagonist) of
its receptors1
• Synthetic prostacyclins and prostacyclin analogues
– act by helping to correct the deficiency of endogenous
prostacyclin seen in patients with PAH
– may be administered by intravenous infusion,2 by
subcutaneous infusion,3,4 or by inhalation5
• Phosphodiesterase-5 (PDE-5) inhibitors
– oral agents which act on NO pathway
1. Humbert M et al. N Engl J Med 2004; 2. Nicolas LB et al. Am J Respir Crit Care Med 2011;
3. Simonneau G et al. Am J Respir Crit Care Med 2002; 4. Barst RJ et al. Eur Respir J 2006;
5. Olschewski H et al. N Eng J Med 2002
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Surgical intervention
• Surgical intervention1
– balloon atrial septostomy
– lung or heart and lung transplantation
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1. Galiè N et al. Eur Heart J 2009
Treatment guidelines: Goal-oriented therapy
• Patients should be monitored regularly and response
to therapy assessed using a range of parameters
• Based on set goals, a patient’s condition at follow-up
may be1:
– stable and satisfactory
– stable but not satisfactory
– unstable and deteriorating
• ‘Stable but not satisfactory’ or ‘unstable and
deteriorating’ → re-evaluation and consideration for
escalation of treatment
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1. Galiè N et al. Eur Heart J 2009
The importance of early identification and
intervention in PAH
• Early diagnosis and therapeutic intervention may
offer an improved outlook for patients
• Prognosis and response to treatment both shown to
be better for patients with less severe disease (i.e.
WHO Functional Class I/II)1
• Early diagnosis challenging: initial symptoms mild
and non-specific
• Many patients are not diagnosed until their disease
is already quite severe2
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1. Sitbon O et al. J Am Coll Cardiol 2002; 2. Humbert M et al. Am J Respir Crit Care Med 2006
Assessing the patient
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Assessing the severity of PAH
• Assessment involves:
–
–
–
–
–
clinical assessment
exercise tests
biochemical markers
echocardiographic assessment
haemodynamic assessments
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Functional class
Functional
Class
I
II
III
IV
Symptomatic profile
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
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
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.
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. Discomfort is increased by any physical
activity
Adapted from guidelines for the diagnosis and treatment of pulmonary hypertension 1
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1. Galiè N et al. Eur Heart J 2009
Functional class and survival
• Even with advanced medical therapy, patients in WHO
FC IV continue to have extremely poor survival rates
1
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1. Humbert M et al. Circulation 2010
6 minute walk test (6MWT)
• Measure of patients’ functional limitations
• Simple, inexpensive, convenient
• Correlate with WHO FC
1
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1. Miyamoto S et al. Am J Respir Crit Care Med 2000
Cardiopulmonary exercise testing
• More sensitive and comprehensive measure of
exercise capacity than the 6MWT1
• Maximal stress test
• Peak O2 consumption (VO2 max)1:
– gold standard for assessing a patient’s exercise capacity
and maximal cardiovascular response
– PAH patients show reduced peak VO2 and this
measurement correlates with a patient’s prognosis
• More difficult to perform and require specialist
equipment
• Not suitable for more severely affected patients
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1. Wensel R, et al. Circulation 2002
Haemodynamic parameters
• Measured by RHC
• Correlate with clinical status, WHO FC, exercise
capacity, and prognosis
• Prognosis is significantly correlated with markers of
right ventricular function1,2,3
• Normalisation of haemodynamics may therefore be
considered a suitable goal or treatment measure
1. Humbert M et al. Circulation 2010; 2. McLaughlin VV et al. Circulation 2002;
3. Benza RL et al. Circulation 2010
.44
Biochemical markers
• Increases in serum NT-proBNP shown to be
associated with prognosis in PAH1
• Serum NT-proBNP < 1400 pg/mL seems to identify
patients with good prognosis1,2
• Cut-off levels still need to be verified in
controlled trials
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1. Galiè N et al. Eur Heart J 2009; 2. Fijalkowska A et al. Chest 2006
PAH-SSc explained
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PAH in patients with SSc (PAH-SSc)
• ~15-25% of all cases of PAH are associated with
connective tissue disease, particularly with SSc1,2
• Patients with SSc who develop PAH have poorer
prognosis than those who do not3,4
• PAH accounts for more than 25% of all SSc-related
deaths5
• Need for early detection and timely treatment before
patients show marked clinical and haemodynamic
deterioration6
1.Humbert M et al. Am J Respir Crit Care Med 2006; 2.Badesch DB et al. Chest 2010; 3.Hachulla E et al.
Rheumatology (Oxford) 2009; 4.Steen VD, Medsger TA. Arthritis Rheum 2003;
5.Steen VD, Medsger TA. Ann Rheum Dis 2007.; 6. Hachulla E et al. Arthritis Rheum 2005
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How is PAH-SSc detected?
• Diagnosis particularly challenging, especially in early
stages
• Symptoms of SSc such as fatigue and dyspnoea are
also symptoms of PAH
• Patients are often diagnosed late when they have
advanced disease with severe clinical and
haemodynamic impairment1
• Screening for PAH in SSc is associated with improved
outcomes1
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1. Humbert M et al. Arthritis Rheum 2011
Screening for PAH in SSc: suggested screening
protocol for the detection of PAH in SSc patients
Figure adapted from: The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicentre nationwide longitudinal study in France1. Hachulla E, de
Groote P, Gressin V, et al. Copyright © 2009, John Wiley and Sons, Inc. Reproduced with permission of John Wiley and Sons, Inc.
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1. Hachulla E et al. Arthritis Rheum 2009
How is PAH-SSc treated?
• Available therapies may improve quality of life and
exercise capacity, and slow disease progression1–5
• Treatment and reassessment of PAH-SSc largely the
same as for IPAH6
• Some special consideration required:
– complications of SSc may affect ability to perform exercise
tests (e.g. 6MWT)7
– potential need to manage multiple complications
(e.g. renal, skin, gastrointestinal)8
• Referral to expert centres recommended
1. Denton CP et al. Ann Rheum Dis 2006; 2. Launay D et al. Rheumatology (Oxford) 2010;
3. Badesch DB et al. J Rheumatol 2007; 4. Badesch DB et al. J Rheumatol 2009; 5. Oudiz RJ et al. Chest 2004;
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6. Galiè N et al. Eur Heart J 2009; 7.Garin MC et al. J Rheumatol 2009; 8. Kowal-Bielecka O et al. Ann Rheum Dis 2009
Further information
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Contacts
For further information visit www.pah-info.com or email
info@pah-info.com
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CH-4123 Allschwil
Switzerland
www.actelion.com
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