A two-stage prospective observational cohort study in scleroderma patients to evaluate screening tests and the incidence of pulmonary arterial hypertension and pulmonary hypertension

• Systemic Sclerosis
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Inclusion criteria

• Male or female
• Age ≥ 18 years
• Patients with definite diagnosis of SSc by American College of Rheumatology (ACR) criteria (18); including all patients with any other connective tissue diseases (CTD) who, in parallel, meet the ACR criteria for SSc (18)
• SSc disease duration > 3 years dated from onset of first non-Raynaud feature
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 60% of predicted

Exclusion criteria

• PH confirmed by RHC before enrolment, i.e. mean pulmonary arterial pressure (mPAP) > or = 25 mmHg at rest or > or = 30 mmHg at exercise, independent of PCWP (11)
• RHC within the 12 months before enrolment
• Use of therapy that is considered definite PAH/PH treatment (19) for any indication, within the 6 weeks before enrolment and/or for a total of more than 6 weeks during the 12 months before enrolment: i.e. endothelin receptor antagonists (ERA; e.g. bosentan, sitaxsentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost), and any experimental PAH/PH drugs. Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted
• Forced vital capacity (FVC) < 40%
• Renal insufficiency, defined as estimated glomerular filtration rate (eGFR) < 40 ml/min/1.73 m2 (20), assessed according to local practice

• Previous evidence or previous diagnosis of clinically relevant left heart disease and other relevant conditions, i.e. at least one of the following:

  • Previous ECHO with estimated left ventricular (LV) ejection fraction < 50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (> 50 mm)
  • Known significant diastolic dysfunction associated with clinical heart failure or PCWP > 15mmHg
  • Known significant coronary disease or significant valvular heart disease
  • Evidence of inadequately treated blood pressure, defined as > 160/90 mmHg and/or blood pressure during exercise > 220/120 mmHg (if evaluated)
  • Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) > 1.2 cm)
  • Patients referred with overt heart failure
  • Known congenital heart defects such as single ventricle, transposition, or Eisenmenger physiology
  • Previous closure of systemic pulmonary shunt, heart valve replacement, or cardiac transplantation
• Pregnancy: pregnancy testing in females with child-bearing potential is mandatory and must be done before enrolment
• Patients unlikely to be available for annual follow up over an anticipated 3 years of study (e.g. survival estimate, psychological, logistics; based on investigator discretion)

Patients with clinically relevant left heart disease as defined above, diagnosed by ECHO at baseline (i.e. after enrolment), will be included in the study.

Additional exclusion criteria after patient enrolment

• During the study, use of therapy that is considered definite PAH/PH treatment (19) is prohibited and will result in discontinuation of the patient from the study, unless the total treatment duration per year is less than 6 weeks. Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
• During the study, use of therapy that is considered definite PAH/PH treatment (19) is prohibited within the 6 weeks preceding the follow-up visits. Violation of this rule will result in discontinuation of the patient from the study.