Pulmonary arterial hypertension (PAH) was considered as the leading cause of morbidity and mortality in systemic sclerosis (SSc) in the last two decades .The patients with SSc and PAH have about 50-60% estimated 3 year survival. There is proliferation and contraction of smooth muscle cells of the pulmonary arterioles in PAH.1

The prevalence of PAH associated with scleroderma is 8-12%.2,3

In patients with diffuse cutaneous SSc (dc SSc) frequency of PAH is almost similar to limited cutaneous SSc.4,5

Mechanisms of pulmonary hypertension in systemic sclerosis:

-PH with proliferative pulmonary vasculopathy = PAH

-PH associated with lung fibrosis due to prominent parenchymal destruction.

– Pulmonary Venous hypertension ( post-capillary PH).

– Post-capillary PH ‘out  of  proportion’  to that expected from PCWP

– pulmonary veno-occlusive disease(PVOD)

– Porto –pulmonary hypertension (POPH)

-Or any combination of these. 1

PVOD is an important point in systemic sclerosis,therefore briefly explained:

In PVOD vascular lesions are more diffuse.In patients with systemic sclerosis and PVOD,there is also arteriolar microangiopathy and it may causes pulmonary edema after treatment with PAH specific vasodilators.6

HRCT findings include septal lines,lymph node enlargement and centrolobular ground glass opacities.7

In PVOD, the pulmonary vasodilators are usually not useful and sometimes can cause pulmonary edema, therefore the diagnosis of PVOD is critical.

Pulmonary hypertension diagnosis

 The symptoms and Clinical examination

The symptoms of PH are non-specific and include dyspnea on exertion, decreasing  exercise  tolerance, fatigue ,syncope and chest  pain.1

The physical signs include a loud P2, left parasternal lift, an RV third heart sound, murmur of tricuspid regurgitation, hepatomegaly and peripheral edema(due to tightness of the skin may not be clear).8

Electrocardiogram (ECG)

Right axis deviation, right ventricle (RV) hypertrophy, P pulmonale,and  right bundle branch block are ECG abnormalities in PH.9

 Chest radiograph

 Findings of chest radiography include central pulmonary arterial dilatation, ‘pruning’ (loss)

 of the peripheral branches ,and in more advanced conditions dilatation of right atrium and ventricle.10

Pulmonary function tests and arterial blood gases

 

These tests reveal the underlying airway or parenchymal lung disease to what extent are involved in development of PH.11,12

Echocardiography

Transthoracic echocardiography is the most effective screening method.

 

Calculation of pulmonary systolic pressure:

The RV-to right atrium( RA) systolic pressure gradient is calculated from:

                       ΔP RV-RA=4(VTR peak)²

VTR peak:the maximum velocity in the tricuspid regurgitant(TR) jet.

To determine right ventricular systolic pressure, right atrial pressure(estimated from the size and respiratory variation in the inferior vena cava),is added to ΔP RV-RA.

Pulmonary artery systolic pressure ( s PAP ) and right ventricular systolic pressure are the same if there is not pulmonic valve stenosis.

In summary:

         s PAP =   ۴  (TRV)²  +  RA  pressure

The assessment of echocardiographic probability of pulmonary hypertension based on tricuspid regurgitation velocity ( TRV) and several additional echocardiographic signs are summarized  in tables 1 and 2.8

Table 1 – Echocardiographic probability of pulmonary hypertension in symptomatic patients with a suspicion of pulmonary hypertension

Peak tricuspid regurgitation        velocity (m/s)	Presence of other echo                  ‘PH signs’ a	Echocardiographic probability of pulmonary hypertension
≤۲٫۸ or not measurable	No	L          Low
≤۲٫۸ or not measurable	Yes	Intermediate
۲٫۹–۳٫۴	No	Intermediate
۲٫۹–۳٫۴	Yes	High
>3.4	Not required	High

PH = pulmonary hypertension

a See next table

Table 2 – Echocardiographic signs suggesting pulmonary hypertension used to assess the probability of pulmonary hypertension in addition to tricuspid regurgitation velocity

A: The ventricles a	B: Pulmonary artery a	C: Inferior vena cava and      right atrium a
Right ventricle/ left ventricle basal diameter ratio >1.0	Right ventricular outflow Doppler acceleration time <105 msec and/or midsystolic notching	Inferior cava diameter >21 mm with decreased inspiratory collapse (<50 % with a sniff or <20 % with quiet inspiration)
Flattening of the interventricular septum (left ventricular eccentricity index >1.1 in systole and/or diastole)	Early diastolic pulmonary regurgitation velocity >2.2 m/sec	Right atrial area (end-systole) >18 cm2
	PA diameter >25 mm.

PA = pulmonary artery.

a Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to alter the level of echocardiographic probability of pulmonary hypertension.

Biomarkers:

Based on Mukerjee et al.,2003 and Williams et al.,2006; N-terminal pro-brain natriuretic peptide(NT-pro BNP) values significantly correlated with haemodynamics.13,2

We can detect an additional 27% of patients with pulmonary hypertension by adding serum NT-pro BNP>100 pg/ml and DLCO<60% of expected to the echocardiographic findings.14

 

Right heart catheterization(RHC)

 

To confirm the diagnosis of pulmonary hypertension and to assess the severity of haemodynamic impairment ,RHC is needed.15During RHC, evaluation of the pressure of PA,PA wedge position,RV and RA must be done.Left heart catheterization in addition to RHC should be considered in patients with echocardiographic signs of systolic and/or diastolic LV dysfunction,as well as in patients with risk factors for coronary artery disease or heart failure with preserved ejection fraction. Blood samples should be taken from the high SVC,IVC,PA and systemic artery for oximetry.8

Hemodynamic definitions of pulmonary hypertension:

Based on 2015European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension, hemodynamic definitions of pulmonary hypertension has been shown in table 3.

Table 3 –Haemodynamic definitions of pulmonary hypertension 

 

Definition	Characteristics
PH	PAPm ≥۲۵ mmHg
Pre-capillary PH	PAPm ≥۲۵ mmHg PAWP ≤۱۵ mmHg
Post-capillary PH Isolated post-capillary PH (Ipc-PH) Combined post-capillary and pre-capillary PH (Cpc-PH)	PAPm ≥۲۵ mmHg PAWP >15 mmHg DPG <7 mmHg and/or PVR ≤۳ WU DPG ≥۷ mmHg and/or PVR >3 WU

CO = cardiac output; DPG = diastolic pressure gradient (diastolic PAP – mean PAWP); mPAP = mean pulmonary arterial pressure; PAWP = pulmonary arterial wedge pressure; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; WU = Wood units.

After above evaluations, risk assessment of patients will be performed based on table 4.8

Table 4 –   Risk assessment in pulmonary arterial hypertension

Determinants of prognosisª (estimated 1-year mortality)	Low risk <5%	Intermediate risk 5–۱۰%	High risk >10%
Clinical signs of right heart failure	Absent	Absent	Present
Progression of symptoms	No	Slow	Rapid
Syncope	No	Occasional syncopeb	Repeated syncopec
WHO functional class	I, II	III	IV
NT-proBNP plasma levels	BNP <50 ng/l NT-proBNP <300 ng/l	BNP 50–۳۰۰ ng/l NT-proBNP 300–۱۴۰۰ ng/l	BNP >300 ng/l NT-proBNP >1400 ng/l
echocardiography	RA area <18 cm2 No pericardial effusion	RA area 18–۲۶ cm2 No or minimal, pericardial effusion	RA area >26 cm2 Pericardial effusion
Haemodynamics	RAP <8 mmHg CI ≥۲٫۵ l/min/m2 SvO2 >65%	RAP 8–۱۴ mmHg CI 2.0–۲٫۴ l/min/m2 SvO2 60–۶۵%	RAP >14 mmHg CI <2.0 l/min/m2 SvO2 <60%

BNP = brain natriuretic peptide; CI = cardiac index; NT-proBNP = N-terminal pro-brain natriuretic

peptide; RA = right atrium; RAP = right atrial pressure; SvO2 = mixed venous oxygen saturation; WHO =World Health Organization.

ª Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but application to individual patients must be done carefully. One must also note that most of these variables have been validated mostly for IPAH and the cut-off levels used above may not necessarily apply to other forms of PAH. Furthermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk.

b Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise stable patient.

c Repeated episodes of syncope, even with little or regular physical activity.

In asymptomatic patients with systemic sclerosis,transthoracic echocardiography is recommended as a screening test.After this,annual screening with echocardiography,DLCO and biomarkers is recommended.8,16,17

In our center ,decision making for the next step after the echocardiography is based on the table 5.

Table 5 – Diagnostic management suggested according to echocardiographic probability of pulmonary     hypertension

Echocardiographic probability of  PH	Next step in management
Low	Echo follow-up should be considered
Intermediate	Further assessment of PH including RHC should be considered
High	RHC

If the patient refuses to RHC,after twice echocardiography within three months with evidence of  intermediate to high echocardiographic probability of pulmonary hypertension and after R/O PVOD, we start the treatment of PH with Phosphodiesterase type5  inhibitors  (Sildenafil or Tadalafil) due to the mechanism of action of these drugs and vascular problem in these patients.

Therapy

Based on 2015 ESC and ERS guidelines for the diagnosis and treatment of pulmonary hypertension, the overall treatment goal in patients with PAH is achieving a low risk status (Table 4), “which is usually associated with good exercise capacity, good quality of life, good RV function and a low mortality risk”.

General measures

The patients should be encouraged to be active to tolerable extent but should avoid excessive physical activities.

The 2015 PH guidelines suggested that oral anticoagulation may be considered on an individual basis and in presence of thrombophilic predisposition.  Class IIb, Level c.8,18,19

Based on the 2015 PH guidelines, diuretic treatment is recommended in patients with signs of RV failure and fluid retention. Class I, Level c.8,20

Continuous long-term O2 therapy is recommended in patients when arterial blood O2 pressure is consistently < 60 mmHg. Class I, Level c.8,21

Iron deficiency has been reported in 46% of patients with SSc-PAH.22

Therefore regular monitoring of the iron status should be considered in these patients. If  iron deficiency is detected, a search for potential causes must be done and treatment should be considered.8

 

Specific drug therapy

Endothelin receptor antagonists

Bosentan , an oral active dual endothelin receptor type A and B antagonist, of this class is recommended.

The starting dosage is 62.5 mg twice daily and increased to 125 mg twice daily after 1month if there are no liver function test derangements or other important adverse effects.1

In patients receiving bosentan, liver function testing should be performed monthly.8

 

Phosphodiesterase type 5 inhibitors

Sildenafil and tadalafil are recommended of this class. Sildenafil,20 mg three times daily and tadalafil,20 mg once daily(and then increase to 40 mg daily) are recommended.8

Most side effects of these drugs are mainly related to vasodilation and including  headache, flushing and epistaxis.1,23

 

 

Prostacyclin analogues and prostacyclin receptor agonists

Iloprost is a chemically stable prostacyclin analogue available as intravenous or aerosol administration.

 

 

Inhaled iloprost

Overall, inhaled iloprost was well tolerated. The inhaled form has been shown to improve exercise tolerance and symptoms when administered 6-9 times daily.1 The most frequent side effects are jaw pain and flushing .

Intravenous iloprost

Intravenous iloprost with starting dose of 0.5ng/kg/min and increase to maximum dose 2ng/kg/min for 6 hour in 5 consecutive days, has shown exercise performance and hemodynamic benefits.1

Transplantation

SSc should not be considered as an a priori contraindication for lung transplantation.8,24

About indications and contraindications for transplantation in patients with systemic sclerosis, decision making must be with a special focus on digestive (gastro-esophageal reflux disease and intestinal disease), cardiac, renal and cutaneous involvement. 8

The treatment algorithm of our center is shown in figure 1.Achievement/maintenance of a low-risk profile (Table 4) considered to be an adequate treatment response .

                      Figure 1 -Treatment algorithm for pulmonary arterial hypertension

In our center assessment of the patients and timing for the follow-up is based on table7.

Table 6 –Suggested assessment and timing for the follow-up of patients

	At baseline	Every 3–۶ monthsa	Every 6–۱۲ monthsa	۳–۶ months after changes in therapya	In case of clinical worsening
Medical assessment and determination of functional class	+	+	+	+	+
ECG	+	+	+	+	+
Echo	+		+	+	+
Right  heart catheterization	+			+	+

  a   Intervals to be adjusted according to patient needs.

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