1. Pulmonary Arterial Hypertension (PAH)
and PAH in Systemic Sclerosis (SSc) 1 1

2. 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

3. Contents Title Slide PAH diagnostic approach 18 Echocardiography 19
Right heart catheterisation 21
Assessing PAH
6-minute walk test 25
How is severity classified? 26
NYHA/WHO classification 27
Treating PAH
How is it treated? 29
PAH-SSc Explained
PAH in Systemic Sclerosis 32
What is Systemic Sclerosis? 33

4. 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? 40
Further information
Actelion contact details 43

5. PAH Explained 5 5

6. 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
What is PAH?
PAH is a syndrome characterised by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular overload and eventually to right ventricular failure and premature death.1 Increased PVR is related to a number of progressive changes in the pulmonary arterioles, including vasoconstriction, obstructive remodelling of the pulmonary vessel wall through proliferation in the various layers of the blood vessel wall (smooth muscle cell and endothelial cell proliferation), inflammation and in-situ thrombosis.
If untreated, PAH carries a very poor prognosis with a median survival of 2.8 years after diagnosis2. This survival figure is comparable with some malignancies.
References
Sitbon et al. Circulation 2005; 111:
2. D’Alonzo GE, Barst RJ. Ann Intern Med 1991; 115:
Sitbon O et al. Circulation 2005
D’Alonzo GE et al. Ann Intern Med 1991

7. PAH: histopathology PAH: histopathology
The main histological features of PAH include medial hypertrophy, intimal thickening, adventitial thickening, plexiform lesions and in-situ thrombosis. The plexifom lesion represents a focal proliferation of endothelial and smooth muscle cells resulting in a complex 3-Dimensional deformation of the vessel and is pathognomonic of PAH.

8. 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
syncope or near syncope
fatigue
peripheral oedema
chest tightness
chest pain on physical exertion
PAH: definition
PAH is defined as a sustained elevation of mean pulmonary arterial pressure (mPAP) of > 25 mmHg at rest or > 30 mmHg while exercise in the presence of a normal pulmonary capillary wedge pressure (PCWP) of < 15 mmHg.1 The earliest symptom of PAH is often dyspnoea experienced on physical exertion. Other symptoms may include syncope or near syncope and fatigue.1,2 Chest tightness and pain similar to angina may occur, particularly on physical exertion. In severe disease, signs of right heart failure (RHF) may emerge.
References
Gaine SP, Rubin LJ. Lancet 1998; 352: 719725.
Barst RJ et al. J Am Coll Cardiol 2004; 43 (Suppl S): 40S47S.
Gaine SP et al. Lancet 1998
Barst RJ et al. J Am Coll Cardiol 2004

9. PAH: classification1 PAH PH associated with left heart disease
Idiopathic PAH
Familial PAH
Associated with:
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
PH associated with left heart disease
PH associated with respiratory disease
COPD
Interstitial lung diseases
PH due to chronic thrombotic and/or embolic disease
Miscellaneous
PAH: classification
Pulmonary arterial hypertension represents Group 1 within the pulmonary hypertension (PH) WHO clinical classification system (Venice 2003 revision).1 Idiopathic PAH, which by definition has no identifiable underlying cause, is one of the more common types of PAH. Familial PAH accounts for at least 6% of cases of IPAH and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in the majority of cases of FPAH.2,3
PAH can also be associated with a number of conditions (Associated Pulmonary Arterial Hypertension; APAH), which together account for most other cases of PAH.
References
Simonneau G et al. J Am Coll Cardiol 2004; 43(Suppl S): 5S34S.
Lane KB et al. Nat Genet 2000; 26(1): 8184.
Deng Z et al. Am J Hum Genet 2000; 67(3): 737744.
Simonneau G et al. JACC 2004

10. PAH: how common is it? PAH is rare Mean age of diagnosis 36 years2
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
PAH: how common is it?
PAH is a rare disease, with an estimated prevalence of 3050 cases per million.1 The prevalence of PAH in certain at-risk groups is substantially higher. For example, in HIV-infected patients the prevalence is 0.46%3; in patients with sickle cell disease the prevalence is 2040%4; and in patients with systemic sclerosis the prevalence has been reported to be up to 16%.5 Idiopathic PAH is more common in young women with a mean age of diagnosis of 36 years2.
References
Peacock AJ. BMJ 2003; 326: 835836.
Gaine SP et al. Lancet 1998; 352: 719725.
Sitbon et al. Am J Resp Crit Care Med 2008; 177:
Lin EE, Rodgers GP, Gladwin MT. Curr Hematol Rep 2005; 4(2): 117125.
McGoon M et al. Chest 2004; 126(1 Suppl): 14S34S.
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

11. PAH: why does it develop?
Exact cause of PAH remains unknown
Endothelial dysfunction occurs early on in the disease process
Endothelial dysfunction results in
reduced production of vasodilators
over production of vasoconstrictors
endothelial and smooth muscle cell proliferation
remodelling of the pulmonary vascular bed and increased vascular resistance
PAH: why does it develop?
The exact cause behind the development of PAH remains unknown. However, research has lead to a better understanding of the underlying mechanisms.
PAH is recognised as a complex, multi-factorial condition involving numerous biochemical pathways and different cell types. Endothelial dysfunction is believed to occur early on in disease pathogenesis, leading to endothelial and smooth muscle cell proliferation and structural changes or ‘remodelling' of the pulmonary vascular bed resulting in an increase in PVR. Vascular remodelling itself involves all layers of the vessel wall and is characterised by proliferative and obstructive changes involving many cell types, including endothelial, smooth muscle and fibroblasts. Inflammatory cells and platelets may also play a significant role in PAH.
Endothelial cell dysfunction results in reduced production of vasodilators, such as nitric oxide (NO) and prostacyclin, and over production of vasoconstrictors, such as thromboxane A2 and endothelin-1 (ET).

12. 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
possesses anti-proliferative properties
vasodilatory effect is mediated by cGMP
rapidly degraded by phosphodiesterases
PAH: why does it develop?
As presented in the previous slide one aspect of PAH pathogenesis is the reduced production of the naturally occuring vasodilators, prostacyclin and nitric oxide.
Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation. It is believed that patients with PAH have low levels of prostacyclin, which could result in vasoconstriction in the pulmonary vasculature and a tendency for smooth muscle cell proliferation and platelet activation, encouraging the formation of thrombi in both the micro-circulation and the pulmonary arteries13. Therapy with synthetic forms of prostacyclin may help to correct this deficiency, although administering this form of treatment is complex46.
Nitric oxide is an endothelial-derived substance that, like prostacyclin, it is a potent vasodilator and also possesses anti-proliferative properties. PAH patients appear to produce insufficient NO and this may contribute to the development of PAH.7 The vasodilatory effect of NO is mediated by cGMP, which is rapidly degraded by phosphodiesterases. Inhibitors of these enzymes promotes the accumulation of intracellular cGMP, thus resulting in vasodilatation.8
References
MacGreggor AJ et al. Rheumatology (Oxford) 2001; 40(4): 453459.
Loyd JE et al. Am J Respir Crit Care Med 1995; 152: 9397.
Rubin LJ. Am J Respir Crit Care Med 2002; 166: 13081309.
Ono F et al. Chest 2003; 123: 15831588.
Galie N, Manes A, Branzi A. Prog Cardiov Dis 2003; 45: 213224.
Clapp LH et al. Am J Resp Cell Mol Biol 2002; 2: 194201.
Gaine SP, Rubin LJ. Lancet 1998; 352: 719725.
Galiè N et al. N Engl J Med 2005; 353: 21482157.

13. 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
PAH: why does it develop?
The pathogenesis of PAH involves the increased production of vasoactive compounds, such as ET-1. Endothelin is produced by the endothelial cells and is essential for maintenance of normal vascular tone and function.  However, high levels of endothelin are seen in patients with PAH due to various aetiologies1-3 and correlate with disease severity,4 resulting in a number of detrimental effects, primarily in the vasculature:5
Fibrosis
Hypertrophy and proliferation of cells, which can lead to thickening, narrowing and occlusion of blood vessels
Inflammation
Vasoconstriction.
Endothelin binds to 2 receptors, ETA and ETB. Both receptors are implicated in PAH and mediate the deleterious effects of endothelin.5 Endothelin receptor antagonism can either mitigate the effects of only one (single ETA antagonist) or both (dual ETA and ETB receptor antagonist) receptor types.
References
Stewart DJ et al. Ann Inter Med 1991; 114: 464469.
Vancheeswaran R et al. J Rheum 1994; 21: 18381844.
Yoshibayashi M et al. Circulation 1991; 84: 22802285.
Galiè N et al. Eur J Clin Invest 1996; 26: A48.
Channick RN et al. Lancet 2001; 358:
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

14. PAH: what are the symptoms?
High resistance to blood flow through the lungs causes right heart dysfunction and produces:1,2
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
PAH: what are the symptoms?
The described changes in the pulmonary vasculature lead to the typical symptoms of PAH. These symptoms are caused by the high resistance to blood flow through the lungs and result in increased strain on the heart. Common early symptoms1,2 include breathlessness (dyspnoea), particularly on physical activity, fatigue, dizziness, syncope, also on physical activity (although this is rare), peripheral oedema and chest pain, again particularly during physical activity.
The symptoms may not be obvious at first and are often attributed to more common conditions such as asthma, general fatigue, or lack of physical fitness. Over time, however, they can become more severe and begin to limit normal activities. As the disease progresses, some patients may experience constant dyspnoea and fatigue so that even simple tasks such as getting dressed and walking short distances become difficult.
References
Gaine SP et al. Lancet 1998; 352: 719725.
Barst RJ et al. J Am Coll Cardiol 2004; 43 (Suppl S): 40S-47S.
Gaine SP et al. Lancet 1998
Barst RJ et al. J Am Coll Cardiol 2004

15. Diagnosing PAH 15 15

16. 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
clinical suspicion
detection of PAH
identification of other causes of PAH
evaluation and classification
PAH: how is it diagnosed?
The early symptoms of PAH (such as dyspnoea, dizziness and fatigue) are often mild and are common to many other conditions. At rest there are often no symptoms and no apparent signs of illness. As a result, diagnosis can be delayed for months or even years meaning that PAH is frequently not recognised until the disease is relatively advanced1; PAH is diagnosed only once other conditions have been investigated and ruled out.
The non-specific nature of symptoms associated with PAH means that the diagnosis cannot be made on symptoms alone. A series of investigations is required to make an initial diagnosis, to refine that diagnosis in terms of clinical class of pulmonary hypertension and to evaluate the degree of functional and haemodynamic impairment. Consequently, it can be useful to adopt a four stage approach:
Clinical suspicion of pulmonary hypertension, such as dyspnoea without overt signs of specific heart or lung disease. Screening of patients with associated conditions (Connective Tissue Disease, Congenital Heart Disease, HIV, Sickle Cell Disease). Incidental findings on examination for other clinical reasons
Detection of pulmonary hypertension using ECG, chest radiograph, which may show evidence of cardiomegaly and enlarged pulmonary arteries and Doppler echocardiogram
Identification of other causes of pulmonary hypertension using pulmonary function tests (PFTs) and arterial blood gas samples, performing ventilation and perfusion lung scans, high resolution computed tomography (HRCT) and pulmonary angiography
PAH evaluation and classification to determine type, functional capacity and haemodynamics by performing blood tests and immunology, HIV test and conducting abdominal ultrasound scan and by carrying out 6 minute walk tests (6-MWT) and peak VO2 and right heart catheterisation and vasoreactivity testing.
Details of some of these investigations and screening tools are shown in the next few slides.
References
Gaine SP, Rubin LJ. Lancet 1998; 352: 719725.
Gaine SP et al. Lancet 1998

17. PAH diagnostic approach
References
ESC guidelines. European Heart Journal 2004; 25:
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. 17
1. ESC Guidelines. European Heart Journal 2004 17

18. 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
PAH: why can it be difficult to diagnose?
Since PAH only affects a relatively small number of patients, it is uncommon for a general physician to see many cases of PAH in their careers.  The majority of patients are diagnosed in a hospital setting but awareness of PAH even amongst specialist health care professionals is low .  Not unsurprisingly, the amount of research published in scientific journals on PAH is also low compared with other conditions.
PAH easily disguises itself due to the similarity of symptoms with other respiratory and cardiology conditions such as asthma, COPD and congestive heart failure. Therefore, patients typically see many health professionals before they are diagnosed with PAH. Diagnosis is also made difficult since there is no simple way to test for PAH.  Procedures such as echocardiogram and right heart catheterisation are required for diagnosis and are usually performed in a specialist hospital setting. 

19. Echocardiography Echocardiography
Echocardiography is one of the techniques available in the screening and subsequent diagnosis of PAH. Compared with a normal heart, the heart of a PAH patient shows considerable enlargement of the right ventricle, a decrease in the size of the left ventricle and an abnormal septal configuration that is consistent with right ventricular overload.

20. Echocardiography: its value as a screening tool
Transthoracic Doppler-echocardiography (TTE) is able to estimate pulmonary arterial systolic pressure, which is equivalent to right ventricular systolic pressure in the absence of pulmonary outflow obstruction, and can provide additional information about the cause and consequences of PH, including right and left ventricular dimensions and function, heart valve abnormalities, right ventricular ejection and left ventricular filling characteristics and presence of a pericardial effusion. In the initial investigation of patients with PAH it is important to obtain adequate images of the right heart. Pulmonary arterial pressure can be estimated from the tricuspid regurgitant jet.
References
ESC guidelines. European Heart Journal 2004; 25:

21. Right heart catheterisation: the diagnostic gold standard
While echocardiography and chest X-ray are useful in the overall evaluation of a patient, right heart catheterisation is required to confirm a diagnosis of PAH1, to assess the severity of haemodynamic impairment and to test the vasoreactivity of the pulmonary circulation. As described in earlier slides, PAH is defined as an mPAP of > 25 mmHg at rest and > 30 mmHg with exercise but with a PCWP of < 15 mmHg. PVR is also >3 Woods units.1
References
Barst RJ et al. J Am Coll Cardiol 2004; 43 (Suppl S): 40S47S.

22. Right heart catheterisation: the diagnostic gold standard
RHC should always assess
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
Right heart catheterisation: the diagnostic gold standard
Right heart catheterisation should always assess right atrial pressure (RAP), pulmonary arterial pressure (PAP [systolic, diastolic and mean]), pulmonary capillary wedge pressure (PCWP), cardiac output / index, pulmonary (PVR) and systemic vascular resistance, blood pressure and arterial and mixed venous oxygen saturation.
A positive vasoreactive response is defined as a reduction in mean pulmonary artery pressure (mPAP) ≥ 10 mmHg to reach an absolute value of mPAP ≤ 40 mmHg with an increase or unchanged cardiac output. A positive response is shown in only 1015% of patients, and sustained response is shown in even fewer (less than 7%).1
References
Sitbon O et al. Circulation 2005; 11: 31053111.
1. Sitbon O et al. Circulation 2005

23. Right heart catheterisation: the diagnostic gold standard
This diagram shows the relative positions of the catheter to record standard haemodynamic measurements.

24. Assessing PAH 24 24

25. 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
6-minute walk test: evaluation of exercise capacity
The 6-minute walk test (6-MWT) to evaluate exercise capacity is reflective of activities of daily living1. The distance a PAH patient can walk in 6 minutes is a critical endpoint in studies evaluating the benefit of different therapeutic options.
To allow meaningful comparisons, it is important that the 6-MWT be performed under supervision according to a standardised protocol.2
A 30 m corridor should be available, marked at 3 m intervals
The patient should rest for at least 10 minutes prior to the test and should not have performed any rigorous exercise within the previous 2 hours
The patient should be asked to rate their baseline dyspnoea
The patient should be instructed to walk to their maximum capacity but not to run or jog; they should be permitted to rest as necessary
The supervisor should count each lap as the patient finishes it
The patient should be asked to rate their dyspnoea at the end of the test
The test should be repeated at approximately the same time of day on each occasion
References
Solway S et al. Chest 2001; 119(1): 256270.
ATS. ATS statement: guidelines for the 6-minute walk test. Am J Crit Care 2002; 166: 111117.
Solway S et al. Chest 2001
ATS. Am J Crit Care 2002

26. 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
PAH: how is severity classified?
Once diagnosed, assessment of PAH usually includes a functional class rating initially devised by the New York Heart Association (NYHA) for Chronic Heart Failure and then adapted for PAH by the World Health Organization (WHO). Functional class measures the severity of PAH and reflects the impact on a patient's life in terms of physical activity and symptoms. There are four classes, with class I being the least severe and class IV being the most advanced.1
References
1. Barst RJ et al. J Am Coll Cardiol 2004;43 (Suppl S): 40S-47S.
Barst RJ et al. J Am Coll Cardiol 2004

27. 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
WHO classification of functional status of patients with pulmonary hypertension
Reference
Barst RJ A et al. J Am Coll Cardiol 2004; 43(Suppl S): 40S-47S.
Barst RJ et al. J Am Coll Cardiol 2004

28. Treating
PAH 28 28

29. 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
PAH: how is it treated?
There is currently no cure for PAH but advances in understanding how the disease develops means that there are now treatments available which have helped to improve prognosis for patients with this disease. The main medical treatment options for patients with PAH are:1
Treatments that are routinely used but with little evidence of an impact on the disease: anticoagulants, such as warfarin, 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 and calcium-channel blockers (CCBs). However, less than 10% of IPAH patients benefit from CCBs therapy. This figure is even lower in other forms of PAH. If not used in appropriate candidates (patients with demonstrated vasoreactivity during right heart catheterisation), CCBs can decrease cardiac output and systemic vascular resistance without any improvement in PAP and PVR and therefore may be deleterious.2
References
Humbert H et al. N Engl J Med 2004; 351:
2. Sitbon O et al. Circulation 2005; 11:
Humbert H et al. N Engl J Med 2004
Sitbon O et al. Circulation 2005

30. 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
Treatments that have been specifically studied in PAH: endothelin receptor antagonists - endothelin is implicated in the pathogenesis of PAH through actions on the pulmonary vasculature. Endothelin is found to be elevated in patients with PAH and levels of endothelin are directly related to disease severity and prognosis. Endothelin receptor antagonists (ERAs) are oral treatments that either block the ETA receptor alone or both the ETA and ETB receptors,1,2 prostacyclin analogues - may be delivered by continuous intravenous or subcutaneous infusion or via an intermittent nebuliser.3 To date, oral agents have shown limited effectiveness and phosphodiesterase 5 inhibitors -induce relaxation and antiproliferative effects on vascular smooth muscle cells by preventing the reduction in levels of cGMP.4
In very severe cases surgical options may be considered:balloon atrial septostomy and heart and lung transplantation.  However, the use of transplantation is constrained by the limited number of donor organs.
References
Channick RN et al. Lancet 2001; 358:
ESC Guidelines. European Heart Journal 2004; 25:
Sitbon O et al. Circulation 2005; 11: 31053111.
4. Galiè N et al. N Engl J Med 2005; 353:
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

31. PAH-SSc Explained 31

32. 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  
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

33. 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
Mouthon L et al. Eur Respir J 2005
Denton CP et al. Trends Immunol 2005

34. 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

35. 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

36. What is Systemic Sclerosis?
The nature of the vascular dysfunction in SSc: 36

37. 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)

38. How common is PAH-SSc?
The overall prevalence of all types of PAH is an estimated 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
Peacock AJ. BMJ 2003
McGoon M et al. Chest 2004

39. 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

40. 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

41. 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

42. Further Information 42 42

43. Contents For further information visit www.pah-info.com
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