Scleroderma, also called systemic sclerosis, is an uncommon autoimmune disease of unknown cause with a complex pathogenesis. More common in women, scleroderma is characterized by endothelial dysfunction resulting in small-vessel vasculopathies, fibroblast dysfunction with resultant excessive collagen production, and fibrosis in addition to immunologic abnormalities.1 Scleroderma is broadly classified into diffuse and limited subtypes. In its limited course it manifests as cutaneous calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias (previously referred to as CREST syndrome).
Scleroderma may affect almost any organ in the body, including the heart and kidneys; however, pulmonary involvement is the leading cause of death in this patient population.2 Patients with scleroderma are prone to developing both interstitial lung disease and pulmonary arterial hypertension (PAH). PAH is more common in patients with the limited form of scleroderma.3 Patients with PAH eventually develop right heart failure with significant morbidity and mortality. The 3-year survival for patients with scleroderma and PAH has been estimated at 56% compared with 94% for those with scleroderma without PAH.4 Many pharmacologic options now exist for treating PAH, so patients with scleroderma should be screened conscientiously for pulmonary disease and managed aggressively to prevent morbidity and mortality.5 Often, late disease recognition leads to more severe disease at presentation, which is correlated with reduced survival.5,6
PAH AND SCLERODERMA
Pulmonary hypertension is defined as a mean pulmonary artery pressure of 25 mm Hg or greater (normal range, 8 to 20 mm Hg) on right heart catheterization. PAH, a disease specifically of the pulmonary microvasculature, has the added criterion of a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mm Hg (normal range, 2 to 15 mm Hg).7 The World Health Organization (WHO) has proposed a classification system for pulmonary hypertension based on common clinical features (Table 1).8,9
Scleroderma-related PAH is a particularly severe complication, with a prevalence of 5% to 12% among patients with scleroderma, and is a leading cause of death in this population.10 Observational studies have demonstrated that mortality remains high in patients with scleroderma and PAH despite current optimized therapy. Over the past decade, the emergence of advanced pulmonary vasodilator therapies has led to an improvement in survival of patients with scleroderma-related PAH, with 1- and 3-year survival rates of 78% and 47%, respectively.11
The diagnosis of PAH may be challenging as dyspnea often is the sole symptom in early stages of the disease. However, certain patient and clinical factors may put patients with scleroderma at a higher likelihood of having PAH. Demographic risk factors include female sex and older age (including older age at onset of scleroderma).12,13 In women, the risk of scleroderma-related PAH has been reported to be increased during the postmenopausal period and linked with a decrease in the protective effects of estrogen on the endothelium.14,15
In addition to certain demographic factors, certain clinical factors also have been linked to the greater risk of development of PAH. These factors include the degree of skin involvement, more severe peripheral vascular disease (Raynaud phenomenon and digital ulcers), as well as the presence of pulmonary fibrosis, microstomia, gastroesophageal reflux, and dysphagia.16
DIAGNOSIS AND MANAGEMENT
PAH typically presents initially with nonspecific symptoms. These symptoms often are difficult to dissociate from those caused by other known underlying cardiopulmonary disorders, making early diagnosis difficult and requiring a high degree of clinical suspicion. For example, patients with scleroderma may develop interstitial lung disease, which also presents with dyspnea. These two conditions must be differentiated, as the treatments are quite different.
The most frequent presenting symptoms of PAH include dyspnea, fatigue, and syncope.9 PAH initially is an indolent condition and as many as 22% patients with scleroderma-related PAH report minimal or no dyspnea.17 In patients with PAH, abnormalities detected on physical examination tend to be localized to the cardiovascular system. Therefore, all patients with scleroderma who present with dyspnea should be further investigated with a detailed history and physical examination. Figure 1 is an algorithm for evaluating suspected PAH.
Also assess the patient's perceived exercise tolerance. Patients with PAH are classified according to WHO Functional Class (Table 2). Patients with severe PAH, RV failure, and elements of syncope are considered WHO class IV at presentation.
A careful physical examination often detects signs and symptoms of PAH and RV hypertrophy. The most common physical findings are:
- an accentuated pulmonic component of the second heart sound
- a systolic murmur—tricuspid regurgitation is common in patients with PAH and is audible as a systolic murmur (Carvallo sign) located along the lower left sternal border that is accentuated with inspiration.18
- edema (such as lower extremity edema) associated with right heart dysfunction.
Other signs and symptoms include right-sided third heart sound, anginal chest pain, hemoptysis, exertional dyspnea, fatigue, syncope, and Raynaud phenomenon.
In patients with severe PAH, the clinical presentation often reflects the degree of right heart failure and includes:
- jugular venous distension with V waves due to tricuspid regurgitation (Moodley sign)
- pulsatile hepatomegaly
- lower limb edema and occasionally anasarca.
Patients with severe PAH may be hypotensive due to decreased cardiac output from RV ischemia. They also have decreased LV stroke volume due to paradoxical shift of the interventricular septum in the left ventricle from RV pressure and volume overload.
The main goal of the diagnostic evaluation in a patient with pulmonary hypertension is to identify or exclude other treatable causes of pulmonary hypertension as the diagnosis of PAH is only made when secondary causes have been clinically ruled out.
ECG and chest radiograph
In patients with pulmonary hypertension, the ECG may demonstrate signs of RV hypertrophy such as tall right precordial R waves, right axis deviation, and RV strain.19 The chest radiograph may provide evidence of underlying lung disease and also show signs of an enlarged pulmonary artery and right heart silhouette.
Arterial blood gas (ABG) analysis
Obtain an ABG analysis to exclude hypoxia and acidosis as contributors to pulmonary hypertension. ABG analysis may be needed as pulse oximetry may not be accurate or possible in patients with Raynaud phenomenon or digital ulcers due to scleroderma.
Pulmonary function testing
These tests provide vital information about possible underlying interstitial lung disease or PAH, and are reliable, readily available, easily interpreted, and relatively inexpensive.20 We recommend that all patients with scleroderma have a baseline set of complete pulmonary function tests (lung volumes, spirometry, and diffusing capacity) and these should be repeated yearly at a minumum.21 Patients with interstitial lung disease typically have a restrictive ventilatory pattern—reductions in total lung capacity or forced vital capacity (FVC)—compared with patients with PAH, who have disproportionate reductions in the diffusing capacity of the lung for carbon monoxide (DLCO). A disproportionate decline in the DLCO relative to the FVC, as demonstrated by an FVC/DLCO ratio of 1.6 or greater, is a strong predictor of later development of PAH.22 Pulmonary function testing is an essential tool for screening patients for scleroderma-related PAH. A declining DLCO and elevated FVC/DLCO ratio also can be helpful in determining contributions of interstitial lung disease.21 Specifically request the DLCO be performed in all patients with scleroderma.
6-minute walk test
This simple and practical test measures the distance that a patient can walk on a flat, hard surface in 6 minutes. The test evaluates the global and integrated responses of all the systems involved during exercise and reflects the patient's functional exercise level for daily physical activities.23 The test has been found to clinically correlate with WHO functional status in patients with scleroderma-related PAH.24 In addition, the test strongly and independently predicts survival in patients with PAH and may be used to monitor therapy or disease progression.25
Transthoracic echocardiography (TTE)
TTE with Doppler flow study is the screening test of choice for pulmonary hypertension but right heart catheterization remains the gold standard for a definitive diagnosis.20 TTE as a screening method can help exclude underlying cardiac disease and hint at the presence of pulmonary hypertension with observational measurement of RV systolic pressure.26,27 The presence of pulmonary hypertension is based on identification of tricuspid regurgitation.20 The addition of mean right atrial pressure to the peak tricuspid jet velocity gives an accurate noninvasive estimate of peak pulmonary pressures. RV dilation and hypertrophy are advanced disease findings. Doppler and pulmonary artery catheter measurement of mean pulmonary artery pressure correlate quite well, with correlation coefficients ranging from 0.89 to 0.97.28 However, TTE may not always accurately estimate pulmonary pressures, and a right heart catheterization is necessary if PAH is suspected.29 A finding of pericardial effusion on TTE predicts poor prognosis in patients with PAH.30
Right heart catheterization
This test is the gold standard for diagnosis and quantitative confirmation of pulmonary hypertension. Patients with severe PAH have a low cardiac index and increased pulmonary vascular resistance. A low pulmonary artery wedge pressure (less than 15 mm Hg) reflects reduced left atrial pressure, effectively excluding left heart dysfunction as the cause of PAH and the low-output state.
CT angiography (CTA) of the chest with high-resolution images is useful for excluding acute pulmonary embolism and other underlying lung conditions such as interstitial lung disease. Ventilation-perfusion (V/Q) lung scanning also can help differentiate chronic thromboembolic disease from PAH.
In patients with PAH, the pulmonary vasculature is the exclusive target of disease. The pathologic vasoconstriction associated with PAH is a prominent feature, so pulmonary vasodilators are the focus of therapy (Table 3).
Calcium channel blockers
These drugs often are used in patients with Raynaud phenomenon who also have scleroderma, and may be helpful in treating PAH.31 In patients who show evidence of an acute hemodynamic response to nitric oxide during right heart catheterization, long-term treatment with calcium channel blockers, administered orally in high dosages, can produce a sustained hemodynamic response and increase survival.32 The use of calcium channel blockers in scleroderma-related PAH is reserved for a very small minority who show vasodilatory response during right heart catheterization.
Phosphodiesterase-5 (PDE-5) inhibitors
At the level of the endothelium, nitric oxide indirectly acts as a potent vasodilator by upregulating the production of cyclic guanosine monophosphate (cGMP). PDE-5 is an enzyme that degrades cGMP, leading to vasoconstriction. Sildenafil, the first PDE-5 inhibitor approved for PAH and the most commonly used, is indicated for patients with WHO functional class II-III symptoms. Patients who are on this medication have shown improvement in symptoms, 6-minute walk test, and WHO functional class.33 Tadalafil, the second PDE-5 inhibitor approved for PAH, has been shown to improve exercise capacity, time to clinical worsening, symptoms, and hemodynamics.34
Endothelin receptor antagonists
Endothelin-1 (ET-1) is a potent vasoconstrictor, and patients with PAH have increased levels of ET-1 in vascular endothelial cells and plasma. Bosentan was the first endothelin receptor antagonist approved by the FDA for the management of PAH in patients with WHO functional class II–IV symptoms.35,36 Clinical trials have shown improvement in clinical outcomes, WHO functional class, exercise capacity, time to clinical worsening, and hemodynamics.37
Another drug in this class, ambrisentan, is a highly selective antagonist with a long half-life that allows once-daily dosing. Data from two studies have shown that ambrisentan taken over 12 weeks significantly improved 6-minute walk in patients with PAH. Associated extension study data also confirmed that continuing treatment for 2 years was associated with sustained improvements in exercise capacity and a reduced risk of clinical worsening and death.33
The newest drug in the class, macitentan, has been shown to significantly decrease morbidity and mortality over the treatment period, and to improve 6-minute walk distance and WHO functional class.38 Patients with PAH suffer disproportionately from a lower mental and physical health related quality of life.39 Macitentan has been shown to improve the overall quality of life for these patients.40
Guanylate cyclase stimulator
Riociguat stimulates soluble guanylate cyclase increases levels of cyclic guanosine monophosphate (cGMP), which results in vasodilation.41 This drug increases exercise tolerance and functional capacity.
Released by the platelets, prostacyclin I2 is a potent pulmonary vasodilator, exerting its effects via adenylate cyclase. Epoprostenol is a prostacyclin I2 derivative that improves exercise capacity, quality of life, hemodynamics, and long-term survival in patients with PAH.42 A thermostable form of epoprostenol can be administered at room temperature, making it easier to use.43
Treprostinil is a prostacyclin analogue that also has been successful in treating PAH by improving exercise capacity, functional class, hemodynamics, and quality of life.44 This drug can be given IV or as a continuous subcutaneous infusion. Inhaled treprostinil is also an option and more recently an oral form of treprostinil has been approved as a first-line therapy for patients exhibiting WHO functional class II or II symptoms.45
Inhaled iloprost has also been shown to induce vasodilation lasting 60 to 120 minutes and has been shown to improve dyspnea scores and hemodynamic variables; however, this drug's major limitation is that it must be inhaled six to nine times daily.46
Prostacyclin receptor agonists
Selexipag is the only drug in this newest class of drug for PAH that has been approved for use in the United States. Selexipag has shown to reduce the risk of death or complications related to PAH.47
Patients with severe PAH may have decompensation despite optimal pharmacologic therapy. Surgical management may be considered for these patients. Atrial septostomy is a catheterization procedure that creates a right-to-left atrial shunt. This decreases preload on the right side of the heart and allows more effective filling of the left side. Indications for atrial septostomy include recurrent syncopal episodes, severe ascites, or clinical deterioration despite maximal drug treatment; the procedure also may be used as a bridge to lung transplantation.48
Lung transplantation is an option in patients under age 65 years who are not improving on disease-specific treatment. Lung transplantation is considered the procedure of choice and is considered if patients who are WHO class III or IV fail to benefit from a 3-month course of medical therapy, taking into consideration the status of the patient's other chronic illnesses.
Certain basic principles can be applied to all patients with PAH, including avoiding high-altitude travel and pulmonary irritants such as tobacco exposure. Evaluate the patient's level of hypoxia using an overnight pulse oximeter or ABG analysis to assess need for supplemental oxygen. Obstructive sleep apnea (OSA) should be ruled out or aggressively treated. A low-salt diet and judicious use of diuretics can help reduce volume overload in patients with pulmonary hypertension and RV failure. As the right side of the heart is dependent on preload, care should also be taken to avoid excessive diuresis and further reduction of cardiac output. Patients with PAH also should be on anticoagulation due to the increased incidence of thromboembolism. Anticoagulation to an international normalized ratio of 2:3 in combination with PAH-specific therapy increases survival.49,50 However, clinicians should keep in mind that the use of anticoagulation in patients with scleroderma should be assessed on a case-by-case basis. The therapeutic goal is centered on optimizing RV preload and systolic function, reducing pulmonary vascular resistance, and maintaining aortic root pressure to allow sufficient right coronary artery filling of the RV.51
In addition to these measures, patients should be enrolled in a pulmonary rehabilitation program. Though once thought to be detrimental to patients with PAH, pulmonary rehabilitation has shown its benefits and increased exercise tolerance in many small-scaled studies.52,53 Patients with PAH also suffer from underlying depression, so should be screened for depression and managed accordingly.54
Scleroderma is an autoimmune condition that can affect any organ in the body. Pulmonary involvement of scleroderma may manifest as PAH and holds an ominous prognosis. Today the pathophysiology of this condition is much better understood and has resulted in many therapies aimed not only at pulmonary vessel dilation but also at preventing pulmonary vasculature remodeling. Appropriate therapy hinges on early identification of PAH in patients with scleroderma. All patients with a history of any form of scleroderma should be screened for PAH and managed expeditiously if it develops.
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