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Introduction

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by skin thickening, Raynaud's phenomenon, and varying degrees of internal organ involvement. Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), the 2 most common lung manifestations, are identified in the majority of scleroderma patients and are the leading causes of mortality (1, 2). PAH is not a rare manifestation of scleroderma. Worldwide, it is estimated that the connective tissue disease–associated PAH cohort accounts for up to 30% of all cases of PAH, and the vast majority of these cases reflect scleroderma-associated PAH (SSc-PAH) (3). Among those with scleroderma, the PAH prevalence is estimated to be 10–15% (4, 5).

The presence of PAH in a scleroderma patient has a devastating impact on survival and, prior to the availability of PAH-specific therapies, the 5-year survival rate was 10% for scleroderma patients with PAH compared to 80% for scleroderma patients without PAH (1, 3, 4, 6–10). SSc-PAH is particularly challenging and even with treatment has a worse outcome compared with idiopathic PAH (iPAH) (8). Not surprisingly for patients with PAH, the presence of advanced disease (functional class III and IV) portends a particularly poor outcome (4, 8, 10).

Over the past 10 years, multiple PAH-specific therapies have become available, and their implementation has led to clinical improvement and an overall improved prognosis in patients with SSc-PAH when compared to historical controls (4, 10–27). The availability of potentially beneficial therapeutic agents argues for approaches that lead to more rapid diagnosis and earlier initiation of medications that may favorably impact on the natural history of the disease.

Recent data support strategies that lead to the earlier detection and earlier intervention with PAH-specific therapies (21). Condliffe et al have shown that survival in “mild” SSc-PAH (functional classes I and II) is significantly improved compared with those with more advanced disease (functional class III and IV) (27). Data from the Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients (EARLY), based largely on subjects with iPAH, show that short-term treatment with bosentan, compared with placebo, in subjects with functional class II PAH leads to significant improvements in cardiac hemodynamics, stabilization of functional class, and less PAH-associated “clinical worsening” (21). Furthermore, the concept that PAH patients with only mild symptoms (functional class II) have “mild PAH” and are unlikely to progress to more advanced disease is challenged by recent data. Fourteen percent of subjects in the placebo arm of the EARLY trial had evidence of clinical worsening of PAH within 6 months, and, in another small series, 75% of patients with functional class II SSc-PAH had significant progression of their disease within 44 months (21, 28).

Because the scleroderma patient is known to be at risk for PAH, there is a unique opportunity to detect PAH earlier than in other cohorts (e.g., idiopathic) that only come to clinical attention once PAH is present. As such, providers involved in the care of scleroderma have an opportunity to identify patients with SSc-PAH at an early stage of their illness through routine screening. Yet data from 2 large PAH registries prove that the majority of scleroderma patients already have advanced PAH (functional class III), similar to iPAH patients, at the time of diagnosis (29, 30). Furthermore, although current guidelines recommend screening for PAH in scleroderma (7), recent data suggest that screening assessments are not routinely done (31).

In this report, we offer a practical approach to screening scleroderma patients for PAH. We highlight specific risk factors associated with the development of PAH, discuss noninvasive modalities used for PAH screening, and provide guidance regarding the use and timing of right-sided heart catheterization (RHC) to confirm a diagnosis of PAH. The approaches outlined emphasize a goal of earlier PAH detection in the scleroderma patient with hopes of earlier implementation of PAH-specific therapies.

Significance & Innovations

  • Pulmonary arterial hypertension (PAH) is a devastating manifestation of systemic sclerosis (scleroderma) and is the leading cause of scleroderma-associated mortality. Because PAH-specific therapies have become available and favorably impact on the disease, vigilant screening to allow for earlier detection is indicated in the care of all patients with scleroderma.

  • Effective screening strategies must incorporate a number of subjective and objective variables, and it can be a challenge to determine when to proceed with right-sided heart catheterization for definitive diagnosis of PAH. In this report, we provide a practical guide for the screening of scleroderma-associated PAH, which should lead to earlier PAH detection.

Definition of Pulmonary Hypertension

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

The terminology and clinical classification of pulmonary hypertension (PH) is complicated and can lead to significant confusion (32). The current classification scheme divides PH into the following 5 distinct clinical groups: 1) PAH, 2) PH associated with disease of the left side of the heart (pulmonary venous hypertension), 3) PH associated with chronic hypoxia (e.g., PH associated with ILD), 4) chronic thromboembolic-associated PH, and 5) PH with unclear or multifactorial mechanisms (e.g., sarcoidosis, lymphangioleiomyomatosis).

It is important to recognize that not all PH is PAH (group 1) and that patients with SSc often have one of the other types of PH, particularly groups 2 or 3 and possibly group 4. Because PAH-specific therapies are currently only approved for patients with PAH (group 1), distinguishing whether a patient has PAH rather than an alternative category of PH is crucial. A diagnosis of PAH absolutely requires cardiac hemodynamic assessment via RHC and is defined by a mean pulmonary artery pressure (mPAP) of ≥25 mm Hg and a pulmonary capillary wedge pressure (PCWP) of ≤15 mm Hg (32, 33). Current criteria no longer include exercise-induced PAP elevation nor do they require pulmonary vascular resistance elevation as part of the PAH definition.

Scleroderma patients commonly have other types of PH, particularly pulmonary venous hypertension (PVH; group 2) or PH associated with ILD (PH-ILD, group 3). In PVH, the elevated pulmonary pressures are a result of either systolic or diastolic dysfunction as confirmed by low cardiac output or an increased PCWP of >15 mm Hg on RHC. With PH-ILD the elevated pulmonary pressures are considered to be a result of chronic hypoxia secondary to underlying lung disease. It is often a challenge to determine the degree of ILD necessary to cause secondary PH. Although rare for scleroderma and typically associated with those with secondary antiphospholipid syndrome, PH secondary to chronic thromboembolic disease (group 4) can also occur (34, 35). In general, the finding of PH should prompt assessments to exclude thromboembolic disease (e.g., with a pulmonary ventilation/perfusion scan) and obstructive sleep apnea (e.g., with polysomnography). Pulmonary venoocclusive disease (PVOD) is a rare and particularly devastating form of PH that can be seen in scleroderma (36). PVOD is often difficult to diagnose, has no known treatment, and is uniformly fatal. The gold standard for diagnosis is a surgical lung biopsy, but because surgical lung biopsy carries significant risk in patients with PH the diagnosis is often presumptive in nature. A diagnosis of PVOD is often considered in the setting of an elevated mPAP with low PCWP and acute clinical worsening after initiation of PAH-specific therapy, and a high-resolution computed tomography (HRCT) pattern of ground-glass mosaic attenuation in the lower lung zones (37).

It must be emphasized that an increase in the estimated pulmonary pressures by echocardiogram (reported either as right ventricular systolic pressure or pulmonary artery systolic pressure) cannot distinguish between PAH and these other classes of PH. Therefore, RHC is absolutely necessary to confirm a diagnosis of PAH and must be performed prior to considering PAH-specific therapy (32).

Symptoms

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

Dyspnea and fatigue are the 2 most common symptoms of PAH, and yet they are both ubiquitous and unreliable among patients with scleroderma. Patients often underreport such symptoms and providers have a difficult time reliably quantifying their severity or progression. It is important for all scleroderma patients to undergo PAH screening, including patients who do not report dyspnea. Many scleroderma patients adapt to their decreased exercise tolerance and rationalize that it is from deconditioning, aging, or “from the scleroderma” and therefore frequently deny breathlessness. It is best not to wait for symptoms of PAH to be obvious before evaluating for its presence.

Physical Examination

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

The physical examination findings of PAH generally reflect right-sided heart failure and are therefore late manifestations of PAH. There are few signs of early PAH on physical examination, but there are several important physical examination findings that suggest the presence of advanced PAH (i.e., features of right-sided heart dysfunction; including lower extremity edema, the murmur of tricuspid regurgitation, jugular venous distension, hepatomegaly, right-ventricular heave, increased intensity of the pulmonic component of the second heart sound, diastolic pulmonic regurgitation murmur, or a prominent A wave in the jugular venous pulse). Any physical examination finding that suggests the presence of right-sided heart compromise should lead to further evaluation. All scleroderma patients should have a yearly physical examination, but hopefully the diagnosis of PAH will be made by screening assessments well before the physical examination indicates right-sided heart dysfunction.

Risk Factors for SSc-PAH

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

All scleroderma patients are at risk for developing PAH, and the presence of certain phenotypic features and pulmonary function test findings should be considered “PAH risk factors” because they are associated with an even greater likelihood of PAH development (Tables 1 and 2).

Table 1. PAH risk factors in scleroderma*
  • *

    PAH = pulmonary arterial hypertension; ANA = antinuclear antibody; DLCO = diffusing capacity for carbon monoxide; ILD = interstitial lung disease; FVC = forced vital capacity.

Limited cutaneous scleroderma
Duration of Raynaud's phenomenon >8 years
Anticentromere antibody positivity
Isolated nucleolar-pattern ANA positivity
Extensive telangiectasia
DLCO <60% predicted in the absence of extensive ILD
FVC%/DLCO% ratio >1.6
Table 2. Features associated with presence of PAH in scleroderma*
  • *

    PAH = pulmonary arterial hypertension; TR = tricuspid regurgitation; RVSP = right ventricular systolic pressure; RA = right arterial; PFT = pulmonary function testing; DLCO =diffusing capacity for carbon monoxide; ILD = interstitial lung disease; FVC = forced vital capacity; BNP = B-type natriuretic peptide; NT-proBNP = N-terminal pro–brain natriuretic peptide.

SymptomsExertional dyspnea
Physical examination findingsEvidence of right-heart compromise; e.g., lower extremity edema, the murmur of TR, jugular venous distension, hepatomegaly, right ventricular heave, increased intensity of pulmonic component of second heart sound, diastolic pulmonic regurgitation murmur, or a prominent A wave in jugular venous pulse
Echocardiographic findingsRVSP >40 mm Hg
 TR jet >3.0 meters/second
 Right ventricular dilation/hypokinesis
 RA dilation
 Pericardial effusion
PFT parametersDLCO <60% predicted in absence of extensive ILD
 FVC%/DLCO% >1.6
Other featuresElevated BNP or NT-proBNP
 Oxygen desaturation with exercise

Classically, patients with longstanding Raynaud's phenomenon, limited cutaneous scleroderma (lcSSc), extensive telangiectasia, and those with anticentromere antibody are the patients with the greatest risk of developing PAH (2, 9, 38–41). Additionally, scleroderma patients with a nucleolar pattern antinuclear antibody (ANA) along with a negative antitopoisomerase (anti–Scl-70) antibody (meaning they have an “isolated nucleolar-ANA”) are at particularly high risk for PAH development. The presence of an isolated nucleolar-ANA accounts for many of the African American patients and those with diffuse cutaneous SSc (dcSSc) that develop PAH (38). Although it is present in only ∼15% of all scleroderma patients, up to 30% of SSc-PAH patients have this isolated nucleolar pattern ANA. Patients with the nucleolar antibodies, anti–U3 RNP, and anti-Th/To have a marked increased risk for PAH (and severe ILD) (38, 42–44). Since the newer immunobead assays do not include these and other scleroderma-specific antigens, the ANAs with these assays are negative in up to 40% of scleroderma patients (45). An immunofluorescent ANA assay that reports both a titer and a pattern is the only way they can be “identified.” We find a nucleolar-ANA pattern to be useful in the usual clinical care of scleroderma patients because it adds valuable information about the risk for ILD and coexistent PAH. We believe that an immunofluorescent ANA pattern should be a component of scleroderma antibody assessments.

It is worth noting that although PAH is usually a relatively late finding in those with established scleroderma (29, 30), it can also be the first clinical manifestation that brings a patient to clinical attention. In these scenarios, it is not uncommon to find a scleroderma-specific antibody (such as anticentromere) and other clues for scleroderma such as Raynaud's phenomenon, digital edema, palmar telangiectasia, or esophageal hypomotility that have been present for many years even if not recognized or diagnosed previously as scleroderma.

A disproportionately low diffusing capacity for carbon monoxide (DLCO) is a risk factor for PH in a scleroderma patient (9). Indeed, Steen has shown that the best predictor for the later development of PH in scleroderma is a declining DLCO (9, 46). The DLCO is usually very low (<50% predicted) at the time of diagnosis of SSc-associated PH, and this is generally in the absence of significant ILD (9, 46). In comparing scleroderma patients with lcSSc involvement who developed PH to those with longstanding lcSSc without PH, Steen found the DLCO was markedly reduced at 52% 5 years prior to the diagnosis of PH compared to a DLCO of 80% in the non-PH lcSSc cohort (9). In serial studies, the DLCO decreased from 80% to 40% through the 10–15 years prior to the diagnosis of PH (9).

PAH Screening: Tools for Noninvasive Assessment

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

Based on the knowledge that all scleroderma patients are at risk for the development of PAH, that later detection is associated with worse outcomes, and that multiple PAH-specific therapies exist, current guidelines advocate for some form of screening assessment for PAH in all patients with scleroderma (7).

Effective screening requires the synthesis of several noninvasive tests combined with the understanding of the scleroderma clinical phenotype. This integration often leads to a picture that is either reassuring for lack of features of SSc-PAH or alternatively is concerning for SSc-PAH and should lead to a decision to proceed with RHC to confirm a diagnosis of PAH.

Pulmonary Function Testing

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

A complete set of pulmonary function tests (PFTs) should be checked at baseline in all scleroderma patients because they provide valuable information about the lung diseases (both ILD and PAH) commonly identified in scleroderma. Restrictive physiology (i.e., reductions in total lung capacity or forced vital capacity [FVC]) is seen with ILD, while disproportionate reductions in the DLCO are more commonly seen with PAH. A disproportionate decline in the DLCO relative to the FVC, as demonstrated by an FVC%/DLCO% ratio >1.6, is a strong predictor of the later development of PAH (9, 46). Because routine spirometry does not include the DLCO, it is important to specifically request the DLCO be performed when ordering PFTs.

Pulmonary function testing is an essential tool for SSc-PAH screening. A declining DLCO and elevated FVC%/DLCO% ratio are very useful as predictors of the presence, or later development, of SSc-PAH and can be helpful in determining contributions of ILD. PFTs are reliable, readily available, easily interpretable, and are relatively inexpensive. We recommend that all scleroderma patients have a baseline set of complete PFTs (lung volumes, spirometry, and diffusing capacity) and these should be repeated yearly in most patients. For those at high risk for ILD progression (e.g., dcSSc or those with a positive antitopoisomerase or isolated nucleolar ANA), one may choose to obtain PFTs even more frequently. Among those without dyspnea or exercise intolerance and >10 years of disease with a persistently normal DLCO over the course of their disease, it is reasonable to spread out PFTs to every 2 years, but they should remain a pivotal part of the overall screening for PAH.

Transthoracic Echocardiography

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

A transthoracic echocardiogram is an essential tool for SSc-PAH screening because it is the best noninvasive assessment for the presence of PH (7). However, it is not uncommon for there to be both an overestimate and an underestimate of the pressures in scleroderma (47). Recent studies have shown that the resting right ventricular systolic pressure (RVSP) is actually higher in scleroderma patients than healthy individuals, even though still in the “normal” range. D'Alto et al recently showed that healthy controls had a mean RVSP of 21 mm Hg compared with 26 mm Hg among those with scleroderma (P < 0.01) (48).

An increased RVSP (also reported as pulmonary artery systolic pressure) may suggest PH, but it is not uncommon to find a label of “pulmonary hypertension” on an echocardiography report when there is any elevation of the estimated pulmonary pressures. We emphasize that a diagnosis of PAH absolutely requires confirmation via RHC, both to confirm an elevated PAP and to determine the PCWP. The exact level of RVSP that should trigger a decision to proceed with RHC is not known; however, our practice is to further investigate an estimated RVSP >40 mm Hg. Furthermore, in addition to an increased RVSP, features on echocardiogram that suggest the presence of PH and warrant consideration of RHC include right atrial dilation, right ventricular dilation or hypokinesis, flattening of the interventricular septum, an accelerated tricuspid regurgitant (TR) jet (>3.0 meters/second), or the presence of a pericardial effusion (9, 16, 49, 50).

Echocardiography is a readily available and affordable test. However, there are significant limitations to its role as a screening tool for SSc-PAH. Echocardiographic estimates of the right side of the heart are limited by technical details that include patient body size, breast tissue, technician variability, technological variability, or interpreter variability. Also, because the vast majority of echocardiographic indications and interpretations focus on the left side of the heart, it is not uncommon to have incomplete assessment or reporting of right-sided findings. Another limitation of echocardiography is that up to 15% of patients do not have a visible TR jet, thereby not allowing for RVSP estimation. Echocardiography both under- and overestimates PH in scleroderma and becomes less accurate when there is advanced parenchymal lung disease (47, 51). Finally, although the echocardiogram can provide an excellent noninvasive assessment of the current status of the right side of the heart, RVSP elevation (unlike the DLCO) has not been shown to be a risk factor for future development of SSc-PAH (9). In fact, up to half of those with an estimated RVSP >35 mm Hg will have values of <35 mm Hg 3 years later (52).

In sum, the echocardiogram provides the most accurate noninvasive view of the right side of the heart and is an essential tool for SSc-PAH screening. We recommend a baseline echocardiogram in all patients with scleroderma. In general, an annual echocardiogram is recommended for all scleroderma patients. However, in our opinion, in those patients with a DLCO >70% and an FVC%/DLCO% ratio <1.6, and without unexplained dyspnea or exercise intolerance, it is reasonable to perform echocardiography at 2-year intervals.

Additional Studies That May Be Useful in Screening for SSc-PAH

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

B-type natriuretic peptide (BNP) and N-terminal pro–brain natriuretic peptide (NT-proBNP).

Elevated BNP or NT-proBNP levels are surrogate biomarkers for myocardial disease and are frequently elevated in patients with SSc-PAH (53–56). They may be useful as an adjunctive component of SSc-PAH screening tools, with a caveat that early patients without significant right-sided heart failure will have normal values. Both proteins reflect generalized cardiac dysfunction (including left-sided heart failure) and are not specific for PAH. However, recent data suggest that among those with SSc-PAH, high levels of BNP or NT-proBNP are associated with a worse prognosis (55).

The specific role of BNP or NT-proBNP testing as a component of SSc-PAH screening remains to be determined (55, 56). Because these assays are widely available, are reproducible, and provide valuable objective information, we encourage their use as an adjunctive component in the screening assessment for SSc-PAH. BNP or NT-proBNP testing may not be covered by insurance as a screening test for SSc-PAH, and this knowledge may impact the decision of whether to obtain these tests. In our opinion, it would be reasonable to obtain a BNP or NT-proBNP level at baseline and then annually in all patients with scleroderma.

6-minute walk test.

A 6-minute walk test (6MWT) can identify exercise intolerance and hypoxemia, but it is not useful as a screening tool for SSc-PAH because it is not specific or sensitive for PAH. Scleroderma patients with and without lung disease have abnormal findings on the 6MWT, and the test does not distinguish between respiratory impairment associated with ILD or PAH (57). Furthermore, the presence of musculoskeletal manifestations of scleroderma (such as arthritis, myopathy, or myositis) may preclude the ability to perform a 6MWT or impact the performance during the test (58). Nevertheless, the 6MWT or a measurement of exercise desaturation may be useful as a screening tool for any significant lung involvement (59). Because Raynaud's phenomenon makes finger-applied pulse oximetry unreliable, a forehead oximetry probe is often necessary to obtain an accurate measure. Although perhaps not a reliable screening test for PAH, when done correctly the 6MWT can provide an accurate, objective, reproducible, and relatively inexpensive tool to help follow the presence of hypoxemia and deconditioning in the same patient over time.

Electrocardiogram.

The electrocardiogram (ECG) is not particularly useful for PAH screening because it does not allow for detection of early disease. In those with advanced PAH, an ECG typically shows signs of right atrial dilation and evidence of right ventricular hypertrophy and strain as evidenced by right axis deviation of the QRS complex (7). A baseline ECG is recommended in patients with scleroderma because it provides useful information that may be pertinent otherwise (e.g., coronary artery disease or arrhythmia) but is not considered a very useful tool when trying to detect early PAH in scleroderma.

Lung imaging.

Thoracic HRCT scans are frequently obtained as a baseline study in scleroderma to assess for the presence of ILD, even if the patient has normal PFTs and lacks respiratory symptoms. HRCT features that suggest PAH and that should prompt more precise PAH assessments include the presence of a widened pulmonary artery diameter of >30 mm (although this measurement seems to be less reliable in patients with ILD [60]), evidence of right-sided heart enlargement, or evidence of pericardial effusion or thickening (49). A plain chest roentgenogram (CXR) is neither effective as a screening tool for ILD nor for assessing for PAH, and as such a normal CXR should not be used to determine whether a scleroderma patient does or does not have significant lung disease.

Novel biomarker for PAH screening?

A novel biomarker in the evaluation of iPAH and SSc-PAH is growth differentiation factor 15 (GDF-15) (61, 62). GDF-15 is a member of the transforming growth factor β “super family” of cytokines and is integral to cell growth and differentiation, cell–cell signaling, and apoptosis regulation. Recent studies have implicated GDF-15 as an inhibitor of polymorphonuclear cell recruitment (63). Recent data demonstrate that GDF-15 is elevated in patients with SSc-PAH (61). GDF-15 levels correlate directly with PAP and the FVC%/DLCO% ratio and are associated with reduced survival. Interestingly, there is increased expression of GDF-15 protein in lung tissue of patients with SSc-PAH, perhaps implicating it in the pathobiology of the disease (61). Further studies are needed to determine whether GDF-15 can be useful as a screening tool for SSc-PAH.

RHC: The Gold Standard for Confirming PAH

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

RHC is the gold standard test for the diagnosis of PH and is absolutely required to confirm a diagnosis of PAH (7, 32, 33). If any patient with scleroderma has unexplained dyspnea with an echocardiogram showing an estimated RVSP >40 mm Hg or evidence of right ventricular dilatation or hypokinesis, RHC should be strongly considered (Table 3). However, as mentioned above, the RVSP is not always reliable or available, so the practitioner often needs to consider other factors to decide whether to proceed with RHC. In our opinion, RHC should also be strongly considered in a scleroderma patient with any “PAH risk factors” (Table 2), particularly those with a disproportionately low DLCO of <60% predicted or an FVC%/DLCO% ratio of >1.6 with unexplained dyspnea, findings of right-sided heart compromise on physical examination, oxygen desaturation on exercise, right-sided heart abnormalities on echocardiogram, an elevated BNP, or NT-proBNP, even with a normal estimated RVSP. An echocardiogram with an estimated RVSP <40 mm Hg without any other PAH-suggestive features should reassure the practitioner that the PAPs are normal.

Table 3. Decision algorithm for screening and performing RHC in scleroderma*
 Low riskMild riskModerate riskHigh risk
  • *

    The presence of echocardiographic features of right ventricular hypokinesis or dilatation or an increased B-type natriuretic peptide (BNP) and N-terminal proBNP in a dyspneic scleroderma patient should lead to right-sided heart catheterization (RHC) irrespective of the estimated right ventricular systolic pressure (RSVP). ANAs = antinuclear antibodies; DLCO =diffusing capacity for carbon monoxide; ILD = interstitial lung disease; FVC = forced vital capacity; PFT = pulmonary function testing.

Dyspnea, or Raynaud's phenomenon duration >8 years, or positive for anticentromere, or positive for isolated nucleolar-ANAsNoYesYesYes
DLCO% (without extensive emphysema or ILD)>70>70<70<60
FVC%/DLCO%<1.6<1.6>1.6>1.6
RVSP, mm Hg<35<35>35>40
Next stepRepeat PFTs annually Repeat echocardiogram in 2–3 yearsRepeat PFTs and echocardiogram annuallyConsider repeat echocardiogram in 3–6 months or proceed to RHCProceed to RHC

As part of the standard RHC procedure, acute vasodilator testing with adenosine, nitric oxide, or prostacyclin may be performed. Even though current guidelines recommend that patients with iPAH undergo vasoreactivity testing as part of their initial RHC, no such consensus exists for SSc-PAH (7). Because vasoreactivity is so uncommon in scleroderma, the lack of its availability as part of the RHC should not preclude performing RHC. Although the RHC is considered an invasive procedure among those experienced with performing the test, the actual procedure has an overall complication rate estimated at 1.1% and the majority of complications are related to venous access (64).

Ultimately, the decision whether to proceed with RHC is individualized to each patient. Collaboration with pulmonary and cardiology colleagues can be useful, and their collective input can help determine whether the pulmonary pressure elevations reflect PAH, PVH, or PH-ILD. We offer an algorithm, with a goal to diagnose PAH at an early stage, to guide decisions on the timing of performing RHC in the scleroderma patient (Table 3).

Discussion

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES

PAH screening in patients with scleroderma is very important because it should allow for earlier detection of the disease, earlier intervention with PAH-specific therapies, and, hopefully, improved survival. Effective screening requires the integration of the clinical scenario, the scleroderma clinical phenotype, PAH risk factor assessment, and the interpretation of results from several noninvasive instruments. When the noninvasive testing suggests PAH, RHC is required to confirm the PAH diagnosis.

Multidisciplinary collaboration among the rheumatologist, pulmonologist, and cardiologist is encouraged to help optimize SSc-PAH screening strategies. Ideally, the decision to proceed with RHC is individualized to each patient, but in general we suggest that practitioners have a low threshold for proceeding with RHC in any scleroderma patient suspected to have PAH. The stakes are too high to miss a chance to detect this devastating disease at an early phase.

REFERENCES

  1. Top of page
  2. Introduction
  3. Definition of Pulmonary Hypertension
  4. Symptoms
  5. Physical Examination
  6. Risk Factors for SSc-PAH
  7. PAH Screening: Tools for Noninvasive Assessment
  8. Pulmonary Function Testing
  9. Transthoracic Echocardiography
  10. Additional Studies That May Be Useful in Screening for SSc-PAH
  11. RHC: The Gold Standard for Confirming PAH
  12. Discussion
  13. AUTHOR CONTRIBUTIONS
  14. REFERENCES
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