Editors' note: This ACR Hotline was contributed by Drs. James Seibold and Joseph Korn. If you have information on an important new topic that you think should be shared with your ACR colleagues, please submit your ideas through Tammy Tilley at the ACR ().

New Therapies for Pulmonary Hypertension in Systemic Sclerosis

August 2002

Pulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (scleroderma). Two-year survival of scleroderma patients with PAH has been 40-55%. The FDA has recently approved three agents for treating this condition, with labeling that specifically includes PAH related to scleroderma.

Pulmonary vascular disease can occur in isolation or in the setting of the later stages of interstitial lung disease complicating both diffuse and limited scleroderma. Initial endothelial cell injury results in abnormal vascular reactivity, related to factors such as local release of the vasoconstrictive mediator endothelin and loss of endothelial derived vasodilators prostacyclin and nitric oxide (NO). Functional lesions progress to structural lesions of arteriolar fibrosis. The newly approved treatments (Table) are well matched to our current understanding of the underlying pathophysiology. Synthetic analogues supplant the loss of endothelial prostacyclin. Endothelin-1, interacting with endothelin A and B receptors on vascular smooth muscle, causes vasoconstriction. Endothelin B receptors are over-expressed in scleroderma lung tissue, and may influence proliferative and inflammatory actions of endothelin (1).

All three agents have been demonstrated in controlled clinical trials to have beneficial effects on exercise capacity and pulmonary hemodynamics. Studies supporting their approval were similar but not identical. Epoprostenol was given to by continuous central infusion to 56 patients with moderate to severe pulmonary hypertension complicating scleroderma (2), and compared in open, randomized fashion with "conventional therapy" (calcium channel blockers, anticoagulants) in 55 matched patients. Over 12 weeks, epoprostenol improved exercise capacity, pulmonary arterial pressure, WHO classification and dyspnea indices. Bosentan was studied in a double-blind, placebo controlled, 16 week trial in 213 patients with severe pulmonary arterial hypertension including 47 with scleroderma (3,4). Effects favoring drug over placebo included improved six minute walking distance, slowing of time to clinical worsening, and improved cardiopulmonary hemodynamics. Treprostinil was studied in a double-blind, randomized, placebo controlled 12 week trial in 470 patients, including 90 with connective tissue disease (5). Exercise capacity, dyspnea indices and pulmonary artery pressure improved significantly in patients receiving drug versus those on placebo. This study included patients with milder disease.

Caveats: None of these studies in scleroderma have sought to demonstrate improved survival. Trials were too short in duration to measure any potential effect on vascular remodeling and improvement of the structural vascular lesion. There are no data regarding earlier treatment in mild disease as a strategy to prevent or delay progression of structural vascular disease. Factors affecting the use of these agents include the short half life of the prostacyclin analogues (epoprostenol 2-5 minutes; trepostinil 3 hours), necessitating continuous infusion, the need for a central line for administration of epoprostenol, the potential teratogenicity of bosentan, and availability issues (e.g. bosentan is distributed only through centralized pharmacies).

Future Directions: There are several therapeutic approaches under investigation. An inhaled prostacyclin analogue, iloprost, may allow ease of administration and minimize some adverse effects seen with systemic use. Oral prostacyclins, and inhaled forms of NO are also under study. Combination therapy with prostacyclins and endothelin antagonists may provide synergistic efficacy. Phosphodiesterase type 5 inhibitors (e.g. sildenafil, brand name ViagraÒ), potentiate and prolong the effects of prostacyclin in the lung, and might be used in single or combination therapy.

The Bottom Line:

• Pulmonary arterial hypertension in scleroderma is under-recognized and under-treated.
• Suspect PAH in scleroderma patients who are dyspneic at rest or with exertion.
• Regular performance of pulmonary function testing is crucial to detecting early disease; suspect PAH if the DLCO is < 55% of predicted or disproportionately low for the FVC.
• Doppler echocardiography and right heart catheterization are useful for diagnosis and staging.
• Results with the newer agents are dramatic and exciting and may offer substantial benefit for affected patients.
  
• Calcium channel blockers work in only 10-20% if patients, but low cost and ease of use make them are a logical first option.
  
• The newer agents are expensive, and there are complex issues with administration and prescription requirements. Use of these drugs may be optimal at centers experienced in the care of patients with PAH.

---James R. Seibold, MD, FACR, Professor & Director UMDNJ Scleroderma Program
---Joseph H. Korn, MD, FACR, Professor & Director, Section of Rheumatology/Arthritis Center, Boston University School of Medicine.
Disclosures: Drs. Seibold and Korn are consultants and funded researchers for Actelion Pharmaceuticals US, which markets bosentan.

July 2002

REFERENCES:
1.Abraham DJ, Vancheeswaran R, Dashwood MR et al: Increased levels of endothelin-1 and differential endothelin Type a and B receptor expression in scleroderma-associated fibrotic lung disease. Amer J Pathol 1997; 151: 831-841.
2. Badesch DB, Tapson VF, McGoon MD et al: Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med 2000; 132: 425-434.
3. Channick RN, Simonneau G, Sitbon O et al: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet 2001; 358: 1119-1123.
4. Rubin LJ, Badesch DB, Barst RJ et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903.
5. Simonneau G, Barst RJ, Galie N et al: Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165: 800-804.

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