A reduction in D l CO may be an early sign Recognizing PAH in patients with systemic sclerosis key words: Pulmonary arterial hypertension, Systemic sclerosis, Scleroderma

June 1, 2006

abstract: Pulmonary arterial hypertension (PAH) is a common complication in patients with systemic sclerosis and is associated with an increased mortality rate. Patients are often asymptomatic early in the disease, but as the disease progresses, exertional dyspnea and fatigue develop. The workup usually includes chest radiography, pulmonary function tests, and Doppler echocardiography. If the results of Doppler echocardiography are consistent with PAH, the patient should undergo right heart catheterization. Patients with mild PAH who demonstrate considerable vasoreactivity are potential candidates for treatment with oral calcium channel blockers. Other therapies that can reduce symptoms and improve exercise tolerance and hemodynamics include bosentan and epoprostenol.

Systemic sclerosis is a heterogeneous autoimmune disorder capable of causing widespread fibrosis of many organs, including the skin, lungs, heart, kidneys, GI tract, and vasculature. It has a peak incidence in the fourth to sixth decades, and women are affected 3 times more often than men are.

Pulmonary involvement is very common in patients with systemic sclerosis and is a major cause of excess morbidity and mortality. The 2 most common manifestations of pulmonary involvement are interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). PAH occurs in more than 35% of patients with systemic sclerosis.1,2 Although PAH can be seen during the course of ILD resulting from diffuse scleroderma, it is more likely to be diagnosed a decade or more after the initial manifestations of limited cutaneous systemic sclerosis. It is usually associated with the presence of anticentromere antibodies.3

Survival is severely diminished when PAH complicates systemic sclerosis (Figure 1). The mortality rate has been reported to be as high as 45% at 1 year, which is significantly higher than that of simi-larly ill patients with primary pulmonary hypertension.4,5

In this article, we will review the evaluation of PAH in patients with systemic sclerosis. We will also discuss treatment options, such as calcium channel blockers and endothelin receptor antagonists.


PAH is diagnosed when mean pulmonary artery pressures exceed 25 mm Hg at rest or 30 mm Hg with exercise. Patients are often asymptomatic early in the disease, but as the disease progresses, exertional dyspnea and fatigue develop. Advanced disease may be associated with dyspnea at rest, chest pain, syncope, or peripheral edema. Patients are functionally classified using the World Health Organization (WHO) system.

Physical examination findings that are consistent with PAH include a right ventricular (RV) heave, a loud pulmonic component of the second heart sound, a murmur of tricuspid regurgitation and, occasionally, pulmonic insufficiency, elevated jugular venous pressure, peripheral edema, and ascites. Objective testing for the evaluation of symptomatic patients should usually include chest radiography, pulmonary function tests, and Doppler echocardiography.

Suggestive findings on a chest radiograph include an enlarged RV silhouette and enlarged pulmonary arteries that rapidly taper, leaving the periphery devoid of vascular markings (Figure 2). The most common pulmonary function abnormality is an isolated reduction in carbon monoxide-diffusing capacity (DlCO), typically below 55% of predicted, or a reduction in DlCO that is out of proportion to the vital capacity.6

Doppler echocardiography can estimate the systolic pulmonary artery pressure by measuring the velocity of the regurgitant jet through the tricuspid valve. It can also be used to assess RV function and to detect RV enlargement or abnormal interventricular septal motion. Echocardiography has been shown to have variable sensitivity and specificity, but it is an acceptable screening tool and is noninvasive.7 Patients in whom PAH is suspected on the basis of a Doppler echocardiography should have the measurement confirmed by right heart catheterization.

Right heart catheterization provides invaluable information and can be performed on an outpatient basis. Direct measurements of right atrial pressure, RV pressure, pulmonary artery pressure, and pulmonary artery occlusion pressures are obtained, as well as calculations of pulmonary vascular resistance and cardiac index. Oximetric readings of oxyhemoglobin saturation are acquired from the right atrium, right ventricle, and pulmonary artery to exclude congenital shunts.

Vasoreactivity, or the ability to lower pulmonary artery pressure and pulmonary vascular resistance with vasodilators, is also assessed. Typically, this is done using a short-acting pulmonary vasodilator, such as intravenous epoprostenol, inhaled nitric oxide, or adenosine. Patients who have primary pulmonary hypertension with vasoreactivity have been shown to have a better prognosis than patients without vasoreactivity, but this difference is less clear in patients with PAH associated with systemic sclerosis.8 Patients with mild PAH who demonstrate considerable vasoreactivity are considered potential candidates for oral calcium channel blockers.


We prefer to give a second trial with intravenous nicardipine during right heart catheterization only to patients who have preserved RV function and vasoreactivity. Those who respond well to this second trial are given slow-release oral nifedipine at a dosage of 30 mg/d. This dosage is slowly increased as tolerated. Nifedipine has short- and long-term benefits in patients with PAH that is associated with systemic sclerosis.

Calcium channel blockers may help alleviate symptoms associated with Raynaud disease as well. The doses needed to successfully treat PAH have a high potential for side effects, such as leg edema and systemic hypotension; thus, patients should be monitored closely.9

Bosentan, an endothelin receptor antagonist, is FDA-approved for the treatment of WHO class III-IV PAH, including that associated with systemic sclerosis. Bosentan improves exercise tolerance and hemodynamics and delays the time to clinical worsening in patients with PAH.10 The starting dosage of oral bosentan is 62.5 mg twice a day; the dosage is usually increased to 125 mg twice a day after 1 month. Potential side effects include liver toxicity, so monthly monitoring of transaminase levels is necessary.

Treatment with continuous intravenous epoprostenol--a synthetic form of prostacyclin--reduces symptoms, increases exercise capacity, and improves hemodynamics in patients with WHO class III-IV PAH that is associated with systemic sclerosis.11 The drug is given by a computerized pump carried in a shoulder purse; the infusion is 2 ng/kg/min, increased until symptoms improve.

Side effects of epoprostenol include flushing, jaw pain, nausea, diarrhea, and bone pain. The epoprostenol solution must be mixed daily and infused through a surgically placed central catheter, predisposing the patient to central venous thrombosis and line sepsis.

Treprostinil is a long-acting analog of prostacyclin approved for continuous, subcutaneous administration in patients with WHO class II-IV PAH, including that associated with systemic sclerosis. It is stable at room temperature and comes preformulated. Because treprostinil is given subcutaneously, an indwelling central venous catheter can be avoided, eliminating the complications discussed above.

The relative efficacy of treprostinil compared with either bosentan or epoprostenol has not been established. Pain at the injection site often limits patient tolerance.

Retrospective data support the use of warfarin titrated to an international normalized ratio of 2.0 to 3.0, but no prospective trials have addressed this.8,12 Supplemental oxygen is indicated when hypoxemia is present. Lung transplantation also is an option for patients with advanced WHO class IV PAH that is refractory to therapy.

We recommend that all patients with WHO class II-IV PAH be referred for initial evaluation and management to centers that specialize in this disorder. This will give them access to those experienced in administering this complex treatment and to consideration for any ongoing clinical trials.



1. Coghlan JG, Mukerjee D. The heart and pulmonary vasculature in scleroderma: clinical features and pathobiology. Clin Opin Rheumatol. 2001;13:495-499.

2. Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest.1996;110: 1515-1519.

3. Hesselstrand R, Scheja A, Shen GQ, et al. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford). 2003;42:534-540.

4. Macgregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford). 2001;40: 453-459.

5. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 2003;123:344-350.

6. Steen VD, Graham G, Conte C, et al. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum. 1992;35:765-770.

7. Denton CP, Cailes JB, Phillips GD, et al. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. 1997;36:239-243.

8. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81.

9. Alpert MA, Pressly TA, Mukerji V, et al. Acute and long-term effects of nifedipine on pulmonary and systemic hemodynamics in patients with pulmonary hypertension associated with diffuse systemic sclerosis, the CREST syndrome and mixed connective tissue disease. Am J Cardiol. 1991;68:1687-1691.

10. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension [published correction appears in N Engl J Med. 2002;346:1258]. N Engl J Med. 2002; 346:896-903.

11. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132:425-434.

12. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587.

13. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol. 1996;35:989-993.