Cardiac manifestations in systemic sclerosis

Table 2 Therapies for systemic sclerosis-related pulmonary arterial hypertension[64-82]

Therapeutic approach	Dosage/comments
Prostanoids
Epoprostenol: a prostacyclin with a very short half-life of 6 min; unstable at pH values below 10.5, requires intravenous administration[54,68]	Starting dose is 1-2 ng/kg per minute, gradually increased up to 25-40 ng/kg per minute
Treprostinil: an epoprostenol analogue with a half-life of 4.5 h, given as a continuous subcutaneous or intravenous infusion in patients with PAH from functional class II, III and IV[54,69]	10-20 ng/kg per minute
Iloprost: a chemically stable prostacyclin analogue with a longer half-life (20–25 min), given as a continuous intravenous infusion for 6-8 h[70]	0.5-3.0 ng/kg per minute
Beraprost: the first oral prostacyclin analogue with vasodilative and antiplatelet action and a half-life of approximately 1 h, indicated in primary and secondary PAH[72,73]	20 μg qid, may be increased by 20 μg/wk. The maximum allowed dose was 120 μg qid with a mean of 80 μg qid
Prostaglandins for inhalation
Iloprost: inhalation has a pulmonary vasodilative potency similar to prostacyclin with longer effects (30-90 vs 15 min); effective in patients with severe PAH functional class III and IV[71]	2.5 or 5.0 mg six or nine times/d; median inhaled dose, 30 μg/d
Endothelin receptor antagonists
Bosentan: the first drug from this group that was approved for treatment of PAH associated with systemic rheumatic diseases in the United States, Canada, Switzerland and European Union; indicated for PAH functional classes II, III and IV[74,75]	62.5 mg bid for 4 wk before titration up to 125-250 mg bid
Sitaxsentan: highly selective endothelin receptor antagonist with a long duration of action; high specificity for type A over type B receptors (6500:1) leads to blockade of the vasoconstrictory effect of endothelin-1 and maintainence of the vasodilative and clearance function of type B receptors[76]	50-100 mg/d
Ambrisentan: antagonist selective for type A over type B endothelin receptors (4000:1)[77]	2.5-10 mg
PDE inhibitors
(PDE degrades cGMP, which mediates the effect of nitric oxide-a potent vasodilator and an inhibitor of platelet activation and vascular smooth muscle)
Sildenafil: a specific inhibitor of the PDE-5 isoform present in large amounts in the lung[78]	20 mg 3 tid
Vardenafil: a PDE-5 inhibitor[80]	20 mg 3 tid
Tadalafil: a specific inhibitor of PDE-5 with a longer half-life (17.5 vs 3.8 h for sildenafil)[79]	20 mg 3 tid
Combination therapy
(oral with inhaled and intravenous drugs)
Sildenafil with intravenous epoprostenol Sildenafil and bosentan[81]
Others
Sodium consumption needs to be restricted to 2400 mg/d in patients with right ventricular failure; digoxin and diuretics when indicated	Saturation < 90% at rest or with exercise; Titration to an international normalized ratio of 1.5-2.5
Surgical options: atrial septostomy, single and double lung transplantation and combined heart and lung transplantation are ultimate therapeutic options in patients with end-stage disease[54]
Routine immunization against influenza and pneumococcal pneumonia
Oxygen therapy
Anticoagulation therapy: (warfarin) in advanced stages with continuous intravenous therapy and in the absence of contraindications
Although inflammation plays a significant role in the development and the progression of PAH, immunosuppression is not a common treatment, as systemic sclerosis-PAH is usually quite refractory to immunosuppressive drugs[82]. However, immunosuppressive treatment has led to improvements in some cases of PAH in other connective tissue diseases (e.g., systemic lupus erythematosus, primary Sjögren syndrome)

PDE: Phosphodiesterase; PAH: Pulmonary arterial hypertension.