Placebo Controlled Trial of Bosentan in Scleroderma Patients

Pulmonary hypertension (PAH) is a common and usually fatal form of lung disease in systemic
sclerosis (SSc). Multiple drugs have been approved for the treatment of New York Heart
Association (NYHA)Class III/IV PAH in scleroderma. Bosentan is an endothelin-1 antagonist
which showed significant improvement in distance walked during 12 week clinical trials in PAH
patients (7). Therapy for asymptomatic systemic sclerosis patients diagnosed incidentally
with PAH (World Health Organization (WHO) Functional Class I) remains controversial. We
hypothesize that asymptomatic or minimally symptomatic patients with systemic sclerosis and
normal resting pulmonary artery pressures who demonstrate an abnormal rise in pulmonary
artery systolic pressure with stress Doppler echocardiography testing represent a subset of
patients who already have pulmonary vascular disease and who are at risk for the development
of severe PAH. We further hypothesize that early identification and treatment of such
patients may retard the progression of that disease.

Hypotheses:

1. Stress echocardiography identifies early pulmonary vascular disease by detecting
exercise-induced pulmonary hypertension in patients with systemic sclerosis.

2. Treatment of exercise-induced PAH with Bosentan will lead to improved exercise endurance
in patients with systemic sclerosis.

Subjects will be recruited from those patients who have had an abnormal exercise test as part
of an earlier study, Exercise Echocardiograms in Scleroderma (IRB# 03-363).

Inclusion Criteria:

- SSc patients > 18 with NYHA functional Class I/II symptoms, informed consent, and who
are willing to participate in the Pulmonary Hypertension Assessment and Recognition of
Outcomes in Scleroderma (PHAROS) long term study (Georgetown IRB 04-227)

- Right heart catheterization with

1. Normal Mean Pulmonary Arterial Pressure (PAP) at rest

2. Mean PAP > 30 with exercise

3. Wedge Pressure < 18

- Entry criteria for participating in the exercise echocardiogram study (Georegtown IRB
03-363)

1. Diffusing Capacity (DLCO) <60 with a Forced Vital Capacity (FVC) >60%, or

2. FVC/DLCO > 1.6, or

3. a resting Pulmonary Arterial Systolic Pressure (PASP)> 40mmHg

Exclusion Criteria:

- Established resting pulmonary hypertension

- Congestive heart failure

- Diastolic dysfunction

- Pregnancy

- Inability to adequately walk/exercise

- Severe liver disease