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Pulmonary arterial hypertension (PAH) is a rare vascular complication of systemic autoimmune diseases, particularly scleroderma and systemic lupus erythematosus (SLE). Early symptoms of PAH, typically mild and protean, include exertional dyspnea and fatigue. However, signs of right heart failure, such as edema and ascites, hepatic congestion, and progressive hypoxemia, develop as the disease progresses. In scleroderma patients, PAH is recognized as a leading cause of death. In addition, the natural history of scleroderma-associated PAH differs from idiopathic PAH or PAH arising in the context of congenital heart disease, progressing more rapidly to heart failure and death in scleroderma patients. In the past decade, PAH treatments have been approved that lessen mortality and improve function among patients with scleroderma-associated PAH, yet pervasive problems, including delays in diagnosis and delays in initiation or limited access to therapy, limit the potential for maximum impact of these drugs. Moreover, PAH continues to be a vexing problem in autoimmune disease due to variations in etiopathogenesis and treatment approaches. While PAH strikes at least 1 in 4 patients with scleroderma, it remains extremely rare among patients with SLE. In many SLE cases, PAH is associated with chronic venous thromboembolic disease and the antiphospholipid antibody syndrome, or an inflammatory systemic vasculopathy that may improve with standard immunosuppressive medications. In contrast, scleroderma-associated PAH does not improve with immunosuppression. Consequently, SLE patients are managed with a different therapeutic approach and may carry a better prognosis than do scleroderma patients with PAH. The following case studies will illustrate key features in the diagnosis and early management of PAH in patients with scleroderma and SLE. The cases will focus on screening techniques and the organized processing of broad differential diagnoses.

Pulmonary Arterial Hypertension

The diagnosis of PAH is defined by hemodynamic criteria obtained during right heart catheterization. Although elevated pulmonary artery pressures (PAPs) may be estimated via Doppler echocardiography, PAH must be confirmed by right heart catheterization measurements of resting mean PAP > 25 mm Hg or an exercise mean PAP > 30 mm Hg, provided that the pulmonary capillary wedge pressure (PCWP) excludes significant pressures transmitted from the left heart (PCWP < 15 mm Hg). Doppler echocardiography is recommended to screen for PAH in scleroderma. In patients with markedly elevated PAP, an echocardiogram is an extremely powerful diagnostic tool, with sensitivity over 90% and specificity of 75%.^[1] However, diagnostic accuracy decreases significantly when right-sided pressures are estimated in the borderline range of 35-45 mm Hg, resulting in a sensitivity of approximately 47% to 58%.^[2]

Studies estimate the prevalence of PAH in scleroderma patients to be between 15% and 50%. The conduct of most of these studies in referral centers raises the possibility of inflated prevalence estimates due to referral bias. However, undiagnosed PAH in subjects with connective tissue disease at the secondary healthcare level of community-based rheumatologists (UNCOVER) study^[3] examined the prevalence of PAH in a collection of 650 cases of scleroderma and mixed connective tissue disease (MCTD) followed in community rheumatology practices. The study detected 89 patients with diagnosed PAH undergoing active treatment. Screening transthoracic echocardiograms performed on the remainder of the cohort revealed an additional 120 patients with estimated peak right ventricular systolic pressures (RVSPs) > 40 mm Hg, a relatively conservative cut-off for the presence of PAH. Thus, UNCOVER estimated a point prevalence of 26.7% among this group of patients. Study weaknesses included the failure to confirm PAH with catheterization, absence of blinding for the echocardiographer, and the use of community echocardiographers without specific training to evaluate for PAH;^[3] however, this prevalence estimate supports the observations of previous studies. Ongoing investigations include prospective cohort studies designed to determine the incidence of PAH and chart the natural history of the disease in the era of effective therapy (for example, the Pulmonary Hypertension Assessment Registry in Scleroderma [PHAROS], www.clinicaltrials.gov).

Prior to the emergence of effective medical treatments for PAH in the 1990s, organ transplant and atrial septostomy were the only viable treatments besides supportive measures that did not significantly affect outcomes, such as supplemental oxygen, anticoagulation, calcium channel blockers, digoxin, and diuretics. In 1991, a published National Institutes of Health-sponsored observational cohort of idiopathic PAH estimated a mortality rate of 48% within 3 years of diagnosis.^[4] Subsequent studies have shown that the prognosis is even worse in scleroderma-associated PAH than in idiopathic PAH or PAH secondary to congenital heart disease.^[5] Moreover, the development of PAH delivers a particularly morbid blow to the prognosis in scleroderma patients, even when compared with the impact of interstitial lung disease on scleroderma mortality. Koh and colleagues^[6] reviewed outcomes in 344 scleroderma patients and reported a median survival of 12 months for scleroderma patients with pulmonary hypertension. In contrast, the study reported over 90% survival at 5 years for scleroderma without lung involvement and 60% survival at 5 years for scleroderma with interstitial lung disease. The reasons for rapid progression and higher mortality rates for PAH in scleroderma patients remain unclear but are likely influenced by comorbidities specific to scleroderma, including pulmonary and myocardial fibrosis.

The complicated pathophysiology of scleroderma is an intertwined network including fibroblast dysfunction, microvascular injury, and autoimmunity.^[7] Deranged fibroblast activity results in widespread tissue fibrosis. Autoimmunity leads to perivascular mononuclear infiltrates; multiorgan inflammation including interstitial ling disease, myositis, and polyarthritis; and loss of peripheral tolerance characterized by autoantibody formation. In addition, systemic microvascular injury, likely beginning with widespread endothelial injury and activation arising early in the disease, comprises a core component of scleroderma pathology with broad consequences, including scleroderma renal crisis and pulmonary hypertension.^[8] The propensity of scleroderma to cause microvascular injury results in an array of clinical features, including striking peripheral vasoreactivity (Raynaud's phenomenon and digital ulcers), mat telangiectasias, nailfold capillary loop disruption and drop-out, gastric antral vascular ectasias, and pulmonary hypertension. This unique microvascular pathology differentiates scleroderma among autoimmune diseases. Notably, most scleroderma-associated PAH develops many years after the onset of scleroderma. Presumably the delay in disease onset reflects cumulative vascular injury, lost capacity to repair vascular injury, or both. Studies of human scleroderma skin xenografts to severe combined immune deficiency (SCID) mice show that signals of hypoxia are maintained in scleroderma skin that is rapidly vascularized by murine endothelial progenitors. Investigators speculate that the defective neovascularization of scleroderma skin may be a consequence of reduced numbers or dysfunction of bone marrow-derived endothelial progenitor cells.^[9] However, the rare observation of severe PAH arising very early in the course of diffuse cutaneous scleroderma suggests that cumulative vascular injury is only one of perhaps many pathological pathways in scleroderma that culminate in PAH.

In the majority of cases, the pathophysiology of scleroderma-associated PAH is considered similar to that of idiopathic PAH. The histology of pulmonary vascular lesions in scleroderma-associated PAH bears striking resemblance to that of the lesions of idiopathic PAH. As occurs in idiopathic PAH, medial and adventitial thickening, intimal hyperplasia, and occasionally plexiform endothelial cell lesions result in profound luminal narrowing or complete obliteration of the vascular lumen in scleroderma-PAH. In scleroderma, pulmonary vascular pathology primarily involves the small arterioles of the pulmonary vascular bed, but appears histologically similar to vascular lesions observed in biopsies of digital ulcers and renal parenchyma involved in scleroderma renal crisis. However, pulmonary vascular lesions in scleroderma appear to accumulate over months and years, while the vascular lesions of scleroderma renal crisis emerge in a fulminant pattern over a matter of days. Moreover, vascular lesions in scleroderma renal crisis, unlike those of PAH, improve with treatment using angiotensin-converting enzyme inhibitors. The reason for the difference in natural history and treatment responsiveness of these pathologically similar lesions remains unknown.

The etiology of pulmonary vascular lesions in scleroderma may be a combination of endothelial injury and failure of natural endothelial repair functions. Endothelial cell activation is a common and early feature of scleroderma pathophysiology; however, the nature of the endothelial injury is uncertain. Existing scleroderma disease models are limited by incomplete recapitulation of the unique and complicated character of human vascular pathophysiology. For example, the most widely used model, the tight-skin mouse (tsk), develops skin and organ fibrosis and autoantibodies against topoisomerase, but there is no significant vascular pathology that reproduces the classic vascular features of human disease. The absence of a representative animal model has compromised progress in research on scleroderma vasculopathy; however, new disease models in development may permit better understanding of vascular pathology.

Imbalance in mediators of vasoconstriction and proliferation of endothelial and smooth muscle cells in the vascular wall appears to be a common problem in most forms of PAH. For example, elevated levels of endothelin-1, a potent vasoconstrictor, are observed in pulmonary vascular endothelial cells in scleroderma, congenital heart disease, and idiopathic PAH.^[10] Imbalances between natural vasoconstrictors, including endothelin-1, and vasodilators, such as nitric oxide and prostacyclin, may influence PAPs in the short term through vasoreactive effects. These pleiotropic signaling molecules also affect the cell cycle, promoting or impairing intimal fibrosis and medial hypertrophy. As a consequence of this ubiquitous final common pathway of PAH pathophysiology, vasoactive mediators including prostacyclin, nitric oxide, and endothelin have become key targets for PAH therapy.

PAH occurs far less frequently in patients with SLE than in those with scleroderma, but the diagnosis is often delayed due to reduced vigilance in SLE compared with scleroderma. Prevalence estimates range from 6% to 15%, although most published studies are affected by referral bias.^[11-13] The etiology and pathophysiology of PAH in SLE is quite varied. In a subset of patients, PAH arises as a consequence of chronic venous thromboembolic disease. These patients often suffer from the secondary antiphospholipid antibody syndrome. Although pulmonary vascular disease similar to idiopathic and scleroderma-associated disease likely occurs in some instances, many cases in SLE are probably caused by vascular inflammation. Pulmonary vascular inflammation has been described in SLE-associated PAH.^[14] Reports of improved hemodynamic parameters following treatment with high-dose corticosteroids or cyclophosphamide provide indirect evidence for an inflammatory vasculopathy.^[12,15] The propensity for SLE-associated PAH to develop as a consequence of chronic venous thromboembolic disease (CVTE) disease or reversible inflammatory vascular injury differentiates it from PAH in scleroderma. Scleroderma-associated PAH, for example, does not respond to immunosuppressive treatment. Sitbon and colleagues^[16] enrolled 28 consecutive subjects with early, untreated PAH secondary to SLE, scleroderma, or MCTD in an open-label study of intravenous cyclophosphamide (22 of 28 subjects also received systemic corticosteroids). While none of the 12 subjects with scleroderma improved, 5 of 12 SLE patients recovered completely, and 3 of 8 MCTD patients responded, suggesting that an autoimmune-mediated inflammatory process was the dominant PAH etiopathogenesis in nearly half of the patients with SLE-associated PAH. Available data estimating mortality rates of 25% two years after diagnosis suggest lower mortality rates in SLE-associated PAH than in scleroderma.^[17] In contrast to scleroderma, the low PAH prevalence in SLE significantly reduces the utility of routine screening by echocardiography. However, PAH should be strongly considered, especially in SLE patients presenting with progressive dyspnea in the context of antiphospholipid syndrome or severe multisystem SLE disease activity.

Ms. Peabody is a 61-year-old woman referred for worsening dyspnea. Approximately 15 years ago, puffy swelling in the hands and fingers developed as the initial sign of scleroderma. She subsequently developed rapidly progressive skin tightness involving the extremities, trunk, and face. Polymyositis confirmed by left deltoid muscle biopsy arose in the second year of her disease. She was treated with corticosteroids and methotrexate with resolution of the myositis. Over the preceding 5 years, her primary complaints included Raynaud's phenomenon with occasional small digital ulcers and symptomatic gastrointestinal dysmotility, treated with proton-pump inhibitors for reflux and dicyclomine for constipation. In 2003, she had routine pulmonary function testing demonstrating a slight reduction in forced vital capacity (FVC) (69% predicted) and diffusion capacity of the lung for carbon monoxide (DLCO) (69% predicted). These results were stable compared with prior studies. At that time, a chest x-ray displayed unchanged interstitial lung markings in the lung bases consistent with stable pulmonary fibrosis. Approximately 12 months ago, she began experiencing palpitations. Electrocardiographic studies confirmed frequent premature ventricular contractions (PVC), but transthoracic echocardiogram at that time was interpreted as "normal." However, in the 6 months preceding her evaluation, the patient has experienced increasing dyspnea with exertion. She has had episodes of palpitations with exercise, but no syncope or chest discomfort. Approximately 6 weeks ago, worsening abdominal distension, described as "gassiness," accompanied by lower-extremity edema, prompted her to seek an evaluation with a gastroenterologist. Esophagogastroduodenoscopy and colonoscopy were performed but no explanatory findings were described. In the past 2-3 weeks the patient's abdominal distension has significantly worsened. A new chest x-ray performed to evaluate her dyspnea suggests "enlargement of the heart shadow," but there was no change in interstitial markings. Repeat pulmonary function tests detected a slight decrease in FVC to 64% predicted and a striking decrease in DLCO (38% predicted) relative to previous studies. Her primary care physician started furosemide to alleviate her lower-extremity edema.

Physical examination reveals a protuberant abdomen with palpable hepatosplenomegaly, shifting dullness, and a fluid wave. In the lower extremities, dense, brawny edema extends to the presacral region. There is a prominent P2, RV heave, and II/VI systolic murmur at the right sternal border. Numerous mat telangiectasias are evident over the face, oropharynx, trunk, and distal upper extremities. Several small digital ulcers accompany sclerodactyly in the fingers. Skin thickening is absent, though some tethering is evident over the distal upper extremities. The facial skin is smooth and atrophic with prominent perioral furrowing. Auscultation of the lungs reveals scattered dry rales at the lung bases.

When considering the cause of dyspnea in scleroderma, recognition of the systemic nature of the disease is critical. Dyspnea may result from primary pulmonary involvement (interstitial lung disease and pulmonary fibrosis), PAH, myopathy, and primary cardiac disease (often myocardial fibrosis with secondary left ventricular [LV] dysfunction). The differential diagnosis can be organized by recognizing the relative risk of these causes of dyspnea. The risk varies depending on disease subtype and duration of scleroderma.

There are 2 major subsets of scleroderma: diffuse cutaneous scleroderma (formerly progressive systemic sclerosis) and limited cutaneous scleroderma (formerly CREST syndrome). These subsets are differentiated by a characteristic distribution of skin thickening, propensity for scleroderma renal crisis, serologic profile, and natural history of disease (Table 1). Of note, the natural history of scleroderma, with particular respect to vascular complications, differs between the limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. Although Raynaud's phenomenon is typically present for years before the diagnosis of lcSSc, it develops simultaneously or even shortly after the onset of other clinical manifestations, such as hand swelling, skin tightness, or gastrointestinal dysmotility in dcSSc. Scleroderma renal crisis, a renin-mediated malignant hypertension characterized by microangiopathic hemolytic anemia and acute renal failure, usually only develops in the first 5-8 years after the onset of dcSSc. Less than 1% of patients with lcSSc develop renal crisis. In contrast to vascular pathology, the natural history of fibrosis is similar between the subsets. For instance, skin scores tend to peak with 2-3 years in both subsets before declining as the skin atrophies, and interstitial lung disease typically runs an early aggressive course with onset within 2-3 years of skin fibrosis and slowing of progressive fibrosis over 5-10 years. Therefore, in this case, it is unlikely that the patient's sudden increase in dyspnea is due to progressive or new-onset interstitial lung disease given the duration of her disease. The pulmonary function testing also provides a clue to the etiology. Although the stable chest radiograph and lung volumes (estimated by FVC) reduce the likelihood that pulmonary fibrosis has progressed, the DLCO has fallen precipitously. Steen and colleagues^[18,19] have shown that the ratio of percent predicted values of FVC:DLCO helps to predict PAH. In their cohort, a rise in FVC:DLCO ratio to > 1.4:1.8 predicted PAH among patients with reduced FVC. In this case, the FVC:DLCO ratio has risen from 1.0:1.68. Unfortunately, there are few other proven clinical predictors of PAH in scleroderma. Retrospective analyses of large scleroderma cohorts at the Johns Hopkins University and the University of Pittsburgh suggest that autoantibodies against vascular antigen B23 and anti-U3 RNP autoantibodies may predict the development of PAH.^[19,20] However, these autoantibodies are not commercially available and occur in only a portion of scleroderma patients who develop PAH. Predictors of PAH prognosis in scleroderma indicate an increased risk for progression to severe, rapidly progressive PAH in patients with later age at onset of PAH, FVC < 50% predicted at onset, and among patients in the limited cutaneous scleroderma subset of disease.^[21]

Table 1. Differentiating Features of Diffuse Cutaneous and Limited Cutaneous Scleroderma

In fact, the physical exam of Ms. Peabody reveals several classic signs of advanced PAH and consequent right heart failure (Table 2). The degree of volume overload is concerning because it reflects the severity of right heart failure. The next step in this patient's evaluation is to obtain baseline laboratory studies to exclude chronic renal or hepatic disease, ultrasound of the liver to exclude vascular obstruction of chronic biliary disease, and, most important, an echocardiogram with a "bubble study" to estimate right-sided pressure, evaluate LV and valvular function, and exclude pericardial and obvious congenital heart disease. The constellation of ascites and severe edema, despite diuretics, rapid progression of dyspnea, and uncertainty about oxygenation during sleep and activity also supports the decision to admit this patient for hospital evaluation.

Table 2. Ms. Peabody's Physical Exam Signs of PAH

After the patient is admitted, a transthoracic echocardiogram is completed (Table 3). It confirms elevated right heart pressures on the basis of severe tricuspid regurgitation and confirms the clinical impression of right heart failure by showing dilatation of both the right atrium and right ventricle and dyskinesis of the interventricular septum. Incidentally noted is mild aortic stenosis. It is unlikely for a congenital heart defect to present this late in life with PAH; however, a bubble study reports that saline microcavitations are normal at rest and with the Valsalva maneuver. Although the most likely etiology of the patient's PAH is scleroderma, it is important to exclude other causes, particularly CVTE, severe pulmonary fibrosis, and sleep apnea. The absence of a history of hypertension, daytime somnolence, obesity, and snoring makes sleep apnea unlikely. A ventilation-perfusion scan is performed and interpreted as low probability for pulmonary embolus. A high-resolution CT scan demonstrates mild pulmonary fibrosis in the lung bases without ground-glass opacities or septal thickening to suggest active interstitial lung disease (Figure). Therefore, the data support a diagnosis of PAH secondary to scleroderma. It is important to note, however, that this patient has several additional processes that could contribute to elevated right heart pressures: mitral valve regurgitation, aortic stenosis, and left ventricular hypertrophy (LVH). Prior to determining treatment, it is crucial to obtain an accurate assessment of the contribution of left heart disease to this patient's right heart pressures.

Table 3. Ms. Peabody's Transthoracic Echocardiogram

Figure. High-resolution CT images of the chest demonstrate mild interstitial changes with minimal honeycomb scar. Ground-glass opacities are restricted to areas of existing fibrosis.

Right heart catheterization is required to confirm the diagnosis of PAH. Catheterization accurately assesses PAPs, provides estimates of cardiac function (cardiac output, cardiac index) and RV failure (ie, right atrial pressure), and detects and measures shunts. By measuring PCWP, right heart catheterization is the optimal tool to assess for LV dysfunction and other sources of pressure transmitted from the left heart to the right heart. Because left heart disease is the most common cause of elevated PAPs, it is critical to estimate the impact of LV function. In addition, catheterization excludes congenital defects and provides a context with which to interpret echocardiogram-estimated right-sided pressures that can vary from catheter-measured pressures by up to 30-40 mm Hg.

In this case, both right and left heart catheterizations were performed to confirm PAH and to assess aortic stenosis. Left ventriculogram and coronary arteriograms were unremarkable, and the gradient across the aortic valve was only 10 mm Hg. Right heart catheterization (Table 4) revealed an elevated mean PAP (35) and normal PCWP. However, there was a striking increase in right atrial pressure (RAP). Although the elevated RAP suggests significant right heart failure, cardiac index was only moderately reduced. There was no evidence of shunting. Vasoreactivity was assessed with inhaled nitric oxide. There was no evidence of vasodilatory response to nitric oxide, which is not unusual in patients with scleroderma. In summary, the evaluation confirms PAH and probably moderate-to-severe right heart failure with no evidence for LV dysfunction or congenital heart disease.

Table 4. Mr. Peabody's Right Heart Catheterization

Additional testing to assess functional status includes a 6-minute walk test. The patient ambulated 306 meters and maintained oxygen saturation between 93% and 95% during exercise, levels identical to her resting oxygen saturation. A serum pro-brain natriuretic peptide (BNP) was elevated to 3371 pg/mL (normal is < 225 pg/mL). Cardiac MRI was performed to evaluate the myocardium. There was no evidence of abnormal signal to suggest myocardial fibrosis due to an infarct or scleroderma, although frequent PVCs require the use of real-time imaging that reduces the sensitivity of cardiac MRI for detecting fibrosis.

There are 5 FDA-approved treatments for PAH (Table 5). Currently, patients with poor prognosis at the time of diagnosis receive treatment with infused prostanoid (subcutaneous trepostinil or intravenous epoprostenol). These patients are typically functional class IV and have echocardiographic and hemodynamic features and clinical evidence of RV failure, specifically elevated right atrial pressure or right atrial enlargement, reduced cardiac index, or pericardial effusion. Patients with less advanced functional class and milder right heart failure may be candidates for treatment with available 5'-phosphodiesterase inhibitors, endothelin antagonists, or inhaled prostanoids. Regardless of the choice of initial treatment, careful observation for disease progression is critical in the management of these patients. They should be evaluated at least every 12 weeks with echocardiogram, 6-minute walk, and assessment of functional status at each visit. Any evidence of clinical decline should be evaluated with another heart catheterization to look for evidence of hemodynamic impact of treatment. Sitbon and colleagues^[22] reviewed the outcome of 178 patients with advanced PAH treated with epoprostenol. Multivariate analysis showed that failure to meet hemodynamic response criteria after 12 weeks of therapy was an independent predictor of death.

Table 5. Approved Therapies for PAH

In this case, a 61-year-old woman with longstanding diffuse cutaneous scleroderma presents with PAH characterized by NYHA and WHO functional class IV (Table 6). Her functional class is based on features including profound fatigue at rest and severely limiting dyspnea at efforts below normal physical activity. Poor prognostic signs include significant elevation of right atrial pressure, reduced cardiac index, and a pericardial effusion.^[4,22] Each of these characteristics has been considered by the American College of Chest Physicians (ACCP) to be a strong predictor of prognosis in PAH on the basis of available evidence (Table 7).^[5] On admission, Ms. Peabody was prescribed nocturnal supplemental oxygen at a dose of 2 liters/minute and began diltiazem (180 mg/day). After catheterization revealed no vasoreactivity to inhaled nitric oxide, the diltiazem was discontinued. PAH treatment was initiated with epoprostenol. In addition, diuretic regimens were initiated resulting in weight loss of 35 pounds over 5 days and resolution of ascites and peripheral edema.

Table 6. PAH Functional Classifications

Adapted by author from: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (Little, Brown & Co.). The 9th edition, revised by the Criteria Committee of the American Heart Association, New York City Affiliate, was released March 4, 1994.

Table 7. American College of Chest Physicians: Predictors of Poor Outcome in PAH

Adapted by author from: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (Little, Brown & Co.). The 9th edition, revised by the Criteria Committee of the American Heart Association, New York City Affiliate, was released March 4, 1994.

Why was Ms Peabody's echocardiogram 12 months prior to presentation reportedly "normal?"

The initial echocardiogram a year before her presentation was performed as part of an evaluation for PVCs, ostensibly to look for structural or wall motion abnormalities. The study reported a peak RVSP of 24 mm Hg without right atrial or RV enlargement or pericardial effusion. In patients with left heart dysfunction or left heart valvular disease, this slight increase in peak RV pressures is not particularly concerning for PAH. However, there were a number of other factors that might have raised concern at that time. First, the echocardiogram was performed as part of an evaluation for palpitations and chest discomfort. It is possible that these symptoms reflected developing PAH. Second, her underlying diagnosis of scleroderma puts her at significant risk of developing PAH. Most scleroderma centers screen for PAH annually in all patients with scleroderma. If serial echocardiograms had been performed, perhaps the results from 12 months ago might have been recognized as a change from previous studies, thus suggesting a trend of increased PAP. This observation should prompt more frequent screening (every 3-6 months) or diagnostic catheterization. It is also important to consider whether the original study adequately assessed the right heart. In patients at risk for PAH from scleroderma, chronic pulmonary emboli, sickle cell disease, HIV, or congenital heart disease, it is important to work closely with the echocardiographer so that an understanding of the goal of the echocardiogram is made clear: to measure elevated right heart pressures and right heart structure to screen for PAH.

What Is the Relevance of the Plasma BNP?

BNP is released by cardiac myocytes stimulated by increased filling pressures.^[23] When ventricular function is compromised, BNP maintains renal function and sodium balance by antagonizing the renin-angiotensin-aldosterone system.^[24] Elevated plasma BNP levels have been reported in patients with idiopathic PAH. Allanore and colleagues^[25] reported on 40 consecutive patients with scleroderma and no evidence of LV dysfunction admitted to their hospital. PAH was diagnosed in 10 patients (25%). In this cohort, elevated plasma N-terminal pro-BNP levels were found to have 90% sensitivity and 90% specificity for the diagnosis of PAH. Moreover, the BNP level correlated with mean PAP (r = 0.44, P = .006). BNP may also be a useful biomarker to assess response to therapy in PAH. In a randomized controlled clinical trial of sildenafil to treat PAH, Wilkins and colleagues^[26] showed that decreases in serum BNP levels correlated with reduced RV mass measures. Diagnostic utility of plasma BNP levels in PAH is limited in patients with LV dysfunction because LV myocytes will contribute to measured levels. However, the BNP may be a useful biomarker in the monitoring of PAH. Additional studies are necessary to clearly define the role of this putative biomarker. Furthermore, disagreement remains regarding the optimal plasma form of the peptide to measure N-terminal-proBNP or BNP. N-terminal pro-BNP is the inactive circulating fragment that results from the cleavage of the pro-BNP prohormone. This peptide differs from BNP, the active hormone, in elimination and half-life.^[23] In this case, there was no evidence of LV dysfunction and the renal function was normal. Therefore, the primary influence on BNP levels is the RV dysfunction. The elevated BNP supports the clinical impression of PAH with right heart failure, but does not obviate the need for catheterization to confirm the diagnosis.

Ms. Smith is a 28-year-old woman referred to clinic for evaluation of weakness and dyspnea. She was originally diagnosed with SLE at age 24 when she developed an erythematous malar rash, subacute cutaneous lupus rash over the trunk and arms, and a symmetrical inflammatory polyarthritis involving the proximal small joints of the hands and the wrists. Serology at the time of diagnosis included a high-titer antinuclear antibody (ANA) and anti-Smith and anti-RNP autoantibodies. Initially she improved with low-dose corticosteroids (prednisone 5 mg/day) and hydroxychloroquine. Over the preceding year she has noticed progressive muscle weakness involving the proximal upper and lower extremities. In the past 4-6 weeks she has noticed rapidly worsening fatigue and malaise, recurrent lupus rash, and dyspnea with exertion. Her examination is remarkable for 4- (on a scale of 0-5) weakness in the deltoids and iliopsoas muscles, synovitis in the wrists and metacarpophalangeal joints, and a serpiginous, erythematous eruption involving the dorsal upper extremities and the upper chest (all sun-exposed areas). There is a minimally prominent P2 and soft systolic murmur along the right sternal border. Examination of the extremities reveals bilateral 1+ pitting edema to the mid-calf. There are no auscultatory findings on lung examination. Laboratory testing shows elevated circulating muscle enzymes and hypocomplementemia (Table 8). Electrocardiogram and chest radiograph were both unremarkable.

Table 8. Ms. Smith's Laboratory Results

The Differential Diagnosis

The differential diagnosis of dyspnea in SLE is predictably a broad list (Table 9). Key considerations include venous thromboembolic disease, particularly in patients with hypercoagulability resulting from antiphospholipid antibodies or the nephrotic syndrome caused by lupus nephritis, interstitial lung disease, anemia, and cardiovascular disease. In this patient, dyspnea is likely attributable in part to her hemolytic anemia and inflammatory myositis (proximal muscle weakness and elevated muscle enzymes). Subsequent testing included an electromyogram and muscle biopsy that confirmed polymyositis. Pulmonary function tests for Ms Smith (Table 10) show a slight reduction in lung volumes, prompting a high-resolution CT scan of the chest that did not reveal any air space or interstitial lung disease. A ventilation-perfusion scan was interpreted as low probability for pulmonary embolus. The patient was treated with high-dose corticosteroids (prednisone 60 mg/day) for her myositis and hemolytic anemia.

Table 9. Differential Diagnosis of Dyspnea in SLE

Table 10. Ms. Smith's Pulmonary Function Tests

After 2 weeks, her hemoglobin, creatine phosphokinase, and aldolase returned to normal, but her dyspnea persisted. Her breathlessness was described as shortness of breath requiring rest after walking less than 2 city blocks. She continued to experience lower-extremity edema to screen for PAH and LV dysfunction revealed elevated RV pressure and enlargement of the right heart chambers (Table 11). In addition, the serum pro-BNP level was elevated (812 pg/mL [normal < 190]). A 6-minute walk distance of 512 meters (72% predicted) suggested reduced exercise tolerance.

Table 11. Ms. Smith's: Baseline Echocardiogram

Although the patient's myositis and hemolytic anemia have responded to corticosteroid treatment, her dyspnea persists. There is no evidence of parenchymal lung disease by imaging. The echocardiogram suggests elevated right-sided pressures with dilatation of the right ventricle. However, the contribution of left heart disease is unclear in this case. Because polymyositis can involve the myocardium, resulting in myocardial stiffness or reduced ionotropic force, a right heart catheterization is critical to fully understand the nature of the elevated right heart pressures (Table 12).

Table 12. Ms. Smith's Right Heart Catheterization

The right heart catheterization confirms mild PAH with significant vasodilatory response to inhaled nitric oxide. The normal PCWP indicates no contribution from the LV dysfunction to the measured right-sided pressures. The patient's myositis and hemolytic anemia are improving with corticosteroids. Azathioprine is added to the immunosuppressive regimen, anticipating the need for a steroid-sparing agent. In addition, the patient's vasoresponsiveness to inhaled nitric oxide suggests that there may be a role for calcium channel blockade to treat the PAH. In idiopathic PAH, calcium channel blocker use may result in improved exercise tolerance by lowering PAPs. It is widely accepted that vasoreactivity measured during catheterization accurately selects patients likely to respond clinically to long-term treatment with calcium channel blockers.^[27] Due to nonspecific vasodilatation and the potential for inducing dangerous hypotension, calcium channel blockers are not used to assess vasoreactivity during the diagnostic catheterization. Current ACCP guidelines favor using inhaled nitric oxide for its specificity for pulmonary vasodilatation and short duration of activity.^[28] Studies restricted to idiopathic PAH suggest that a subset of patients (12.6% to 26.7%) will display vasoreactivity on testing.^[27,29] A retrospective review from Sitbon and colleagues^[30] found that only 38 of 70 patients who displayed vasoreactivity showed sustained clinical responses to long-term calcium channel blocker treatment. Unfortunately, there are few data regarding the impact of calcium channel blockers in SLE-associated PAH, although vasoreactivity may be far less common in secondary PAH (associated with HIV, congenital heart defects, and autoimmune diseases) than in idiopathic PAH. ACCP guidelines do not recommend using calcium channel blockers for PAH that is complicated by right heart failure.^[28] In this case, the patient had evidence of early right heart failure (RV and right atrial dilatation, septal dyskinesis, mild peripheral edema), but poor prognostic features were not present (significant elevation of right atrial pressure, pericardial effusion, significantly shortened 6-minute walk distance). On the basis of the data from Sanchez and colleagues^[16] suggesting that as many as half of SLE-associated PAH cases respond to immunosuppressive therapy without the need for PAH-specific medications, such as endothelin antagonists or prostanoids, the aggressive immunosuppressive regimen (high-dose corticosteroids and azathioprine) is considered the primary PAH therapy in this patient. However, in view of the vasoreactivity, diltiazem is initiated at a dose of 60 mg/day and titrated to 240 mg/day over 4 weeks.

A repeat echocardiogram after 10 weeks of corticosteroids and calcium channel blockade showed a decline in estimated peak RV pressures, but the RV enlargement persisted (Table 13). Over the next 4 weeks, the corticosteroids were gradually tapered. After an additional 8 weeks of diltiazem and azathioprine, a follow-up echocardiogram demonstrated resolution of RV and right atrial enlargement and continued fall in estimated PA pressures. The 6-minute walk distance rose steadily to 512 meters and further to 517 meters. Currently, the patient does not experience any dyspnea with exertion or show any evidence of RV failure.

Table 13. Ms. Smith's First Follow-up Echocardiogram

This case demonstrates the importance of considering PAH in SLE patients with dyspnea and illustrates the potential of therapeutic efficacy of immunosuppression. The case also reinforces the importance of careful prospective evaluation. If the patient had declined clinically at any point, reevaluation of therapy may have included adjustments to the immunosuppressive regimen -- for example, slowing the steroid taper or starting cyclophosphamide, or adding an approved PAH therapy.

Summary

PAH should be considered as a cause of dyspnea in patients with scleroderma or SLE. Its prevalence in scleroderma is high enough to warrant routine, annual screening with echocardiograms in all patients. If elevated right heart pressures are suggested by echocardiogram in any patient, diagnostic right heart catheterization is required. In addition, etiologies including chronic venous thromboembolic disease and congenital heart defects should be evaluated in all patients diagnosed with PAH. Treatment options will vary depending on PAH severity, prognostic characteristics, and underlying primary disease and the duration of that disease. Many cases of SLE-associated PAH may respond to immunosuppression, while scleroderma-associated PAH will require approved PAH-specific therapy. A close interaction among cardiologist, pulmonologist, and rheumatologist is likely to enhance the quality of care delivered to patients with PAH.

This program was supported by an independent educational grant from Actelion.

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