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  2. Abstract


Screening allows for early management of pulmonary arterial hypertension (PAH), a severe complication of systemic sclerosis (SSc). Since no consensus has been reached on the method and criteria for optimal screening, we sought to develop an algorithm based on symptoms, Doppler echocardiography, and right heart catheterization (RHC) for application to a nationwide multicenter SSc population in France.


This prospective study was conducted from September 2002 to July 2003 by experts at 21 SSc centers. At each center, SSc patients without severe pulmonary function abnormalities underwent Doppler echocardiography by an experienced cardiologist. Patients with a peak velocity of tricuspid regurgitation (VTR) of >3 meters/second or 2.5–3 meters/second with unexplained dyspnea were asked to undergo RHC to confirm PAH according to international guidelines.


Of the 599 patients analyzed, 29 had known PAH and 33 had suspected PAH, based on Doppler echocardiography, and underwent RHC. Of these 33, 18 were found to have PAH, 3 had left ventricular dysfunction, and 12 had no PAH. Newly diagnosed cases of PAH were of mild severity (mean ± SD pulmonary artery pressure [mPAP] 30 ± 9 mm Hg, mean ± SD total pulmonary resistance [TPR] 524 ± 382 dynes × second/cm5). Hemodynamic findings in patients with known PAH were mPAP 49 ± 17 mm Hg and TPR 1,007 ± 615 dynes × second/cm5. The estimate of PAH prevalence was 7.85% (95% confidence interval 5.70–10.00).


This screening algorithm, based on dyspnea, Doppler echocardiographic evaluation of VTR, and RHC, enabled early detection of PAH at a mild stage. Whether mild PAH will evolve to severe PAH in reported cases and whether this early diagnosis translates into improved prognosis for patients with mild PAH will be evaluated in the ongoing 3-year followup of this cohort.

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, characterized by a progressive increase in pulmonary vascular resistance, ultimately causing right ventricular failure and death. PAH is defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest or ≥30 mm Hg during exercise, with a normal pulmonary artery wedge pressure (<15 mm Hg). In systemic sclerosis (SSc) patients, the development of PAH is known to have a major impact on outcome and survival (1–3). Moreover, SSc patients with PAH are at higher risk of death than patients with idiopathic PAH, despite similar hemodynamic patterns and treatments, with respective estimated 1-year survival rates of 55% and 84% (4). Early diagnosis and specific management of this severe complication, prior to the development of end-stage pulmonary vascular disease, are of utmost importance in SSc (5).

International guidelines (6) recommend systematic screening of SSc patients, with annual Doppler echocardiography, in order to detect PAH. However, these guidelines do not provide recommendations with regard to thresholds and optimal parameters to be used to define possible PAH on Doppler echocardiography (6). In the literature, peak velocity of tricuspid regurgitation (VTR) (7), tricuspid gradient (8), or estimated systolic PAP (sPAP) (9) have been used. Similarly, various thresholds for tricuspid gradients have been tested (range 30–45 mm Hg) (8). Right heart catheterization (RHC) is the gold standard for definite diagnosis of PAH but, because of its invasive nature, is only recommended in those patients with high probability of having PAH as suggested by Doppler echocardiography. Consequently, the accurate determination and applicability of the optimal criteria for suspecting PAH in high-risk populations is clinically relevant.

In the setting of a nationwide awareness and screening effort relative to PAH and SSc, we developed an algorithm based on symptoms, Doppler echocardiography, and RHC that we applied prospectively in a multicenter cohort of SSc patients in France. We report the results of this screening program in terms of clinical relevance of the chosen echocardiographic criteria and thresholds, PAH prevalence, and profile of the patients diagnosed.


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  2. Abstract

Selection of patients.

This prospective study was conducted between September 2002 and July 2003 in 21 French university hospitals that have personnel experienced in SSc management and that follow up the largest numbers of patients with active SSc. Each center established a multidisciplinary team, including SSc experts (internists, dermatologists, or rheumatologists), echocardiographers, and PAH specialists. The investigators (Itinerair-Scleroderma Investigators Group) are listed in Appendix A. All SSc patients receiving medical care at these centers were invited to participate in this study as part of their regular followup. Consecutive patients fulfilling the American College of Rheumatology (formerly, the American Rheumatism Association) criteria (10) were enrolled after giving their informed consent. They were classified as having diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) (11).

With the goal of assessing a homogeneous population, SSc patients with known severe pulmonary function abnormalities (defined as pulmonary function test results for forced vital capacity [FVC], total lung capacity [TLC], or forced expiratory volume in 1 second [FEV1] <60% of predicted) were excluded since they are prone to develop another type of pulmonary hypertension, secondary to chronic respiratory disease (12). Patients with known severe cardiac disease were not enrolled, in order to exclude potential postcapillary causes for elevated PAP. For the estimation of the prevalence of PAH, patients with known RHC-proven PAH were included with the understanding that this pulmonary hypertension was not associated with interstitial lung disease.

Study design.

The screening algorithm included evaluation of dyspnea, Doppler echocardiography, and RHC (Figure 1). Dyspnea was evaluated according to the New York Heart Association (NYHA) functional class, as commonly used for the assessment of PAH (6). Data on the following parameters were collected: baseline demographic and SSc characteristics, exposure to risk factors for PAH (such as use of appetite suppressants), time since onset of Raynaud's phenomenon and time since the first symptom other than Raynaud's phenomenon, nature of this first symptom (distal skin sclerosis or calcification, digital ulcer, pulmonary fibrosis, esophageal dysfunction, or telangiectasia), the Rodnan skin score (13), and signs and symptoms suggestive of PAH. Unless performed within the previous 6 months, pulmonary function tests were repeated, and the following data were collected: TLC, FVC, FEV1/FVC, diffusing capacity for carbon monoxide (DLCO), DLCO/alveolar volume, and blood gases.

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Figure 1. Screening algorithm for diagnosis of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). VTR = peak velocity of tricuspid regurgitation; mPAP = mean pulmonary artery pressure; PAWP = pulmonary artery wedge pressure. Right heart catheterization was performed except when Doppler echocardiography provided evidence of left heart disease.

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In patients with documented PAH, no additional tests were performed; hemodynamic data from the most recent RHC were used. The independent Ethics Committee of the Centre Hospitalier Universitaire de Lille approved the study protocol.

Doppler echocardiography.

All SSc patients meeting the inclusion criteria were referred to a senior cardiologist in each center, who performed a complete time–motion-bidimensional and Doppler echocardiography examination with standard views and procedures, after the patient had rested for 20 minutes. Particular attention was accorded to the identification and quantification of tricuspid regurgitation. Color-flow Doppler was used to obtain the best possible alignment between the tricuspid regurgitation and the Doppler ultrasound beam. Continuous-wave Doppler was used for acquisition of spectral envelopes of the highest quality to measure the VTR. PAH was suspected in patients with VTR >3 meters/second, or with VTR of 2.5–3 meters/second associated with unexplained dyspnea, and warranted confirmatory RHC (Figure 1). As suggested by Berger et al (14), it was assumed that PAP was normal in patients in whom VTR could not be quantified, provided the right ventricle was normal.

The echocardiographer was blinded with regard to the dyspnea status of the patients. In addition, all echocardiographic results were centrally reviewed for quality and consistency by a cardiologist (PdG) who was also blinded with regard to clinical features. No echocardiography had to be repeated or excluded as a result of inadequacies based on the central review.

Right heart catheterization.

All patients with echographically suspected PAH underwent RHC to confirm the diagnosis, unless they had any evidence of left heart disease (Figure 1). Experienced clinicians performed the RHC according to standard techniques, using a Swan-Ganz catheter. Mean right atrial pressure, systolic, diastolic, and mPAP, as well as pulmonary artery wedge pressure (PAWP) were measured. Cardiac output was measured using the thermodilution method (liters/minute) and the cardiac index was calculated as cardiac output/body surface (liters/minute/m2). Total pulmonary resistance (TPR) (dynes × second/cm5) was calculated as (mPAP/cardiac output) × 80. Pulmonary vascular resistance (PVR) (dynes × second/cm5) was calculated as ([mPAP − PAWP]/cardiac output) × 80.

When the resting mPAP was <25 mm Hg, hemodynamics during exercise were measured, when possible. The arms or legs (depending on the site of venous puncture for RHC) were moved, with a level of exercise corresponding to 30–40W for 6–10 minutes (maximum oxygen uptake 500 ml/minute/m2). Based on current guidelines, PAH was defined as mPAP ≥25 mm Hg at rest or ≥30 mm Hg during exercise, with PAWP <15 mm Hg. When PAWP exceeded 15 mm Hg, left heart disease was diagnosed.

Statistical analysis.

The prevalence of PAH (detected by RHC) was calculated as the ratio of patients with either known or newly diagnosed PAH over the eligible population. The analyzed population included all patients who met the inclusion criteria and underwent all study procedures, and patients with known PAH.

SAS software, version 8.2 (SAS Institute, Cary, NC) was used to perform statistical analyses. Results are expressed as means ± SD for continuous variables and as numbers (percentages) for binary and categorical variables. All comparisons were 2-sided. P values less than 0.05 were considered significant. Continuous variables were compared with Student's t-test or analysis of variance, adjusted for age where appropriate. Categorical variables were compared using a chi-square test or Fisher's exact test. The Cochran-Mantel-Haenszel test was used for stratified analysis. The parameters collected were subjected to post hoc multivariate analysis to assess their potential predictive value for PAH detection.


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  2. Abstract

Study population.

Seven hundred nine consecutive patients were enrolled. Among them, 60 were excluded based on abnormal pulmonary function test results in 43, a diagnosis other than SSc in 15, and left heart disease in 2, and 50 patients did not undergo the requested protocol investigations and were excluded from analysis. Thus, 599 patients satisfied the protocol criteria and were retained for the analysis; their clinical characteristics are reported in Table 1.

Table 1. Clinical characteristics of the entire study population and according to the type of SSc*
ParameterAll SSc patients (n = 599)dcSSc (n = 165)lcSSc (n = 434)P
  • *

    Except where indicated otherwise, values are the mean ± SD. Chi-square test or Fisher's exact test, as appropriate, was used to compare categorical variables between systemic sclerosis (SSc) patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc); Student's t-test or analysis of covariance adjusted for age was used for continuous variables. RP = Raynaud's phenomenon.

Age, years54.7 ± 13.053.3 ± 12.855.2 ± 13.10.11
Female, no. (%)502 (83.8)128 (77.6)374 (86.2)0.01
Age at first non-RP SSc symptom, years46.2 ± 13.843.7 ± 13.947.1 ± 13.70.008
Age at SSc diagnosis, years47.8 ± 13.845.6 ± 14.048.7 ± 13.60.02
Time since first onset of RP, years14.1 ± 12.111.9 ± 11.414.8 ± 12.20.01
Time since first non-RP symptom, years8.5 ± 7.99.3 ± 8.48.2 ± 7.80.04
Rodnan score13.4 ± 10.925.6 ± 12.38.8 ± 5.4<0.0001
Prior digital ulcer(s), no. (%) of patients317 (53.3)100 (61.4)217 (50.2)0.02

Doppler echocardiography findings.

Among the 599 patients, 29 had known PAH and 570 were screened for PAH. VTR could not be measured in 114 patients (no tricuspid regurgitation was present in 91, and image quality was too poor to allow precise measurements of VTR in 23). These patients had no indirect evidence of pulmonary hypertension, since the size of their right heart chambers was comparable with that of the patients with a VTR <2.5 meters/second. Thirty-seven patients had VTR >3 meters/second or had VTR 2.5–3 meters/second associated with unexplained dyspnea. Of these 37 patients, 4 had echocardiographic evidence of left ventricular dysfunction which was not previously known; PAH was suspected in the remaining 33 patients. Of note, the frequency of dyspnea (NHYA functional class II, III, and IV) increased with the levels of VTR, as follows: dyspnea was present in 29.3% (139 of 475) of those with VTR ≤2.5 meters/second, 40.6% (43 of 106) of those with VTR 2.5–3 meters/second, and 72% (13 of 18) of those with VTR >3 meters/second.

Right heart catheterization.

All of the 33 patients in whom PAH was suspected underwent RHC. Among them, PAH was confirmed in 18 cases (individual data are reported in Table 2), based on a resting mPAP of 25–34 mm Hg in 9 patients, 3544 mm Hg in 4 patients, and ≥45 mm Hg in 1 patient, and an mPAP of ≥30 mm Hg during exercise in 4 patients, despite a resting mPAP <25 mm Hg. Of these 18 patients, 6 had a VTR between 2.5 and 3 meters/second (range 2.6–2.95), with dyspnea ranging from NYHA functional class II to class IV. The corresponding resting mPAP in these patients ranged from 15 to 35 mm Hg, with PAH diagnosed based on mPAP during exercise in 1 patient.

Table 2. Individual clinical, echocardiographic, and hemodynamic data on the 18 patients with newly diagnosed PAH*
PatientRight heart catheterizationNYHA classDoppler echocardiography
Resting mPAP (exercise mPAP), mm HgmPAWP, mm HgCardiac output, liters/minuteTPR, dynes × second/cm5PVR, dynes × second/cm5VTR, meters/secondRAD, mmRVD, mm
  • *

    PAH = pulmonary arterial hypertension (defined as mPAP [mean pulmonary artery pressure] ≥25 mm Hg at rest or mPAP ≥30 mm Hg during exercise, with normal pulmonary artery wedge pressure [PAWP] [<15 mm Hg]); TPR = total pulmonary resistance (calculated as [mPAP/cardiac output] × 80); PVR = pulmonary vascular resistance (calculated as [{mPAP − PAWP}/cardiac output] × 80); NYHA = New York Heart Association; VTR = peak velocity of tricuspid regurgitation; RAD = right atrium longitudinal diameter; RVD = right ventricle diastolic diameter; ND = not done.

125 (ND)95.30377242IV2.6048.326.8
226 (ND)146.45322149II2.6648.232.5
335 (ND)146.02465279III2.9038.928
428 (ND)125.80386221II2.9050ND
515 (32)75.22230123II2.9544.834.4
626 (32)134.08510255II2.9544.437.7
727 (ND)69.27233181II3.105940
825 (44)64.80417317III3.104222.5
927 (29)126.69323179II3.1054.434.8
1022 (35)105.90298163ND3.1536.227.7
1133 (ND)69.10290237I3.2352.523.7
1224 (33)94.30447279ND3.2839.930.9
1327 (ND)75.60386286III3.3038.835.5
1421 (35)85.40311193II3.504731
1555 (ND)92.801,5711,314IV3.8656.439.3
1637 (ND)115.81509358II3.995736
1741 (ND)52.481,3231,161III4.105644
1840 (ND)103.101,032774III4.4055.336.8

The diagnosis of PAH was excluded based on RHC in the remaining 15 patients (left heart disease resulting in postcapillary pulmonary hypertension in 3, and normal baseline or exercise hemodynamics in the remaining 12). It is interesting to note that among those 12 patients, mPAP was ≥20 mm Hg in 6 cases, which is above physiologic range and accepted as a diagnosis threshold for pulmonary hypertension associated with other conditions (15, 16).

Patients with PAH.

Among the 18 newly diagnosed PAH patients, 15 (83.3%) described dyspnea, which was characterized as NYHA functional class II in 8, III in 5, and IV in 2. Right heart catheterization showed that patients with newly diagnosed PAH had PAH of mild severity, with a mean ± SD mPAP of 30 ± 9 mm Hg, cardiac index of 3.18 ± 1.00 liters/minute/m2, and TPR of 524 ± 382 dynes × second/cm5.

The clinical characteristics of the patients with newly diagnosed PAH and of those with no PAH are reported in Table 3. Patients with PAH were older at study entry and at the time of SSc diagnosis. Their body mass indexes were higher, but none of them took appetite suppressant drugs. The nature of the first SSc symptom other than Raynaud's phenomenon did not differ between the 2 groups. The frequencies of prior digital ulcers (44.4% versus 53.7%; P = 0.44) and active digital ulcers at study entry (5.6% versus 12.5%; P = 0.71) did not differ between groups. A higher percentage of these newly diagnosed PAH patients presented with symptoms and signs of right heart failure, and the right heart dimensions in this group compared with those who had no PAH were larger on echocardiography, as follows: mean ± SD right atrial transversal diameter 38.7 ± 8.32 mm versus 34.3 ± 7.0 mm (P = 0.01), mean ± SD right atrial longitudinal diameter 48.3 ± 7.2 mm versus 42.1 ± 7.2 mm (P < 0.0001), and mean ± SD telediastolic right ventricular diameter 33.0 ± 5.9 mm versus 30.0 ± 6.6 mm (P = 0.061).

Table 3. Clinical characteristics, signs, symptoms, and pulmonary function test results in patients with newly diagnosed PAH versus those with no PAH (n = 566)*
ParameterNewly diagnosed PAH (n = 18)No PAH (n = 548)P
  • *

    Four patients with left heart disease were excluded. Except where indicated otherwise, values are the mean ± SD. P values were determined by analysis of covariance or Student's t-test. PAH = pulmonary arterial hypertension; SSc = systemic sclerosis; RP = Raynaud's phenomenon; DLCO = diffusing capacity for carbon monoxide.

Age, years65.0 ± 11.754.1 ± 12.9<0.001
Female, no. (%)16 (88.9)465 (84.9)1.00
Body mass index, kg/m226.6 ± 5.923.9 ± 4.50.014
SSc subtype, no. (%) limited10 (55.6)409 (74.6)0.10
Age at first non-RP SSc symptom, years52.0 ± 14.745.7 ± 13.80.07
Age at SSc diagnosis, years57.4 ± 13.447.3 ± 13.60.003
Time since first non-RP symptom, years11.9 ± 12.68.5 ± 7.80.29
Rodnan score13.8 ± 8.613.0 ± 10.70.77
Dyspnea, no. (%)15 (83.3)147 (26.8)<0.0001
Fatigue, no. (%)11 (61.1)182 (33.2)0.014
Palpitations, no. (%)6 (33.3)78 (14.2)0.037
Syncope or presyncope during exercise, no. (%)3 (16.7)15 (2.7)0.016
Chest pain, no. (%)1 (5.6)17 (3.1)0.45
Lower limb edema, no. (%)6 (33.3)37 (6.8)<0.001
Hepatojugular reflux, no. (%)4 (22.2)4 (0.7)<0.0001
Jugular venous distention, no. (%)4 (22.2)6 (1.1)<0.0001
DLCO, % of predicted56.2 ± 23.372.6 ± 18.0<0.0004
Patients with DLCO <60%, no. (%)13 (72.2)149 (27.2)<0.0001
PaO2 + PaCO2, mm Hg111.3 ± 12.6127.5 ± 15.1<0.0001

In patients with PAH, the DLCO values were lower and the percentage of patients with low DLCO (<60%) was significantly higher. In a multivariate model to identify factors predictive of PAH in SSc patients, a DLCO <60% was found to be significantly associated with the probability of PAH (odds ratio 9.23, 95% confidence interval [95% CI] 2.73–31.15). In the 29 patients with known PAH (hemodynamic parameters at last right heart catheterization mPAP 49 ± 17 mm Hg, cardiac index 2.76 ± 0.73 liters/minute/m2, TPR 1,007 ± 615 dynes × second/cm5), the mean ± SD time since its diagnosis was 17.8 ± 20 months (range 1.3–96.2 months). Treatment for PAH consisted of bosentan (82.8%), diuretics (58.6%), anticoagulants (41.4%), prostanoids (13.8%), or calcium-channel blockers (10.3%).

Overall, 47 patients (of the 599 SSc patients with no severe pulmonary function abnormalities) presented with PAH, yielding a prevalence of 7.85% (95% CI 5.70–10.00). Had the mPAP threshold of 20 mm Hg been used to define PAH as in other studies (17), the PAH frequency in our population would have been 8.84% (95% CI 6.57–11.11).


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  2. Abstract

This is the first French prospective nationwide multicenter study devoted to screening for PAH in SSc. Our study used a predefined algorithm which included symptoms, Doppler echocardiography, and RHC. This approach allowed early detection of PAH.

Published studies describing PAH prevalence in various SSc populations were all performed at single centers, and either prospective (7, 9, 18) or retrospective (1, 19) in design, with relatively small numbers of patients (range 34–152) recruited over 3–9 years. A recent report described the prevalence and outcome of SSc-associated PAH in 722 patients enrolled at a single center over a 4-year period (18). As a comparison, the overall multicenter population of 709 SSc patients in our study was enrolled within 11 months.

The authors of a recent epidemiologic study using capture-recapture analysis estimated the prevalence of SSc in the French county of Seine Saint-Denis to be 158.3 cases/million inhabitants (20). With an estimated 7,000 adult SSc patients in France, we have enrolled ∼10% of them in this study, which represents a significant proportion of the French SSc population. The study was conducted in the 21 largest SSc centers, and showed that this screening approach is applicable in all clinical settings.

Doppler echocardiography is a recognized useful tool for screening patients with underlying diseases (such as SSc) that are associated with a high risk of developing PAH (6). The echocardiographer's experience is crucial for the accurate ultrasonographic identification of the tricuspid regurgitation jet and, hence, detection of PAH. In particular, the tricuspid gradient may be underestimated if the regurgitant jet is not fully aligned or its signal weak. Notably, tricuspid regurgitation of measurable quality was recorded in 59–73.5% of standard examinations (14, 21), but reached 86% when the Doppler evaluation was performed by a highly experienced echocardiographer (21). We were able to determine VTR in 81.5% of our patients, highlighting the good quality of the echocardiographies in this study. Current guidelines confirm the need to rely on an experienced sonographer (22, 23).

Although the foundation for screening patients is Doppler echocardiography, the international guidelines available when we initiated the study did not provide detailed recommendations on the best parameter and threshold to be used to identify potential cases of PAH (6). Since the Doppler-measured right ventricular–to–right atrial pressure gradient (calculated with the modified Bernoulli equation 4 × VTR2) correlates well with sPAP recorded during RHC (24), we based our diagnostic algorithm on VTR, rather than sPAP, as assessed by echoDoppler. This estimation of sPAP requires the addition of the estimated right atrial pressure–to–transtricuspid gradient pressure from VTR. Right atrial pressure is estimated subjectively based on the degree of inferior vena cava collapse during inspiration and ranges from 0 to 15 mm Hg, therefore representing a source of some variability for this hemodynamic calculation and possibly contributing to an over- or underestimation of sPAP (8). To overcome this weakness, some authors have arbitrarily assigned a value of 0 mm Hg to the right atrial pressure (18), which is obviously acceptable among healthy subjects but not among patients.

With regard to optimal threshold to detect suspected PAH with Doppler echocardiography, various cutoff values have been used in the literature. Our threshold of a VTR ≥2.5 meters/second is derived from previous publications (9, 25). Mukerjee et al compared the abilities of Doppler echocardiography versus RHC to discriminate between the presence and absence of PAH in 137 SSc patients (8). They applied various VTR thresholds to test the sensitivity and specificity of the two techniques. Doppler echocardiography was highly specific at high thresholds (97% with a VTR ≥3.35 meters/second) but at the expense of a 42% false-negative rate. Pertinently, when echocardiography and clinical findings were combined (NYHA functional class for dyspnea grading), >90% of patients with advanced PAH were identified. The authors concluded that Doppler echocardiography, as an adjunct to clinical evaluation, is the optimal screening approach for identification of PAH in SSc patients.

RHC is the gold standard for PAH diagnosis (22, 23). It allows direct measurement of pulmonary pressures and excludes postcapillary causes of pulmonary hypertension, which, as shown herein and by others, are not always detected by echocardiography. RHC is to be performed by experienced physicians; under these conditions, the safety of this procedure has been demonstrated (26). Left heart disease was one of the main differential diagnoses for patients recruited for this study, and the difficulties of excluding diastolic left heart dysfunction based on noninvasive tests further emphasizes the importance of systematically obtaining complete measurements during RHC. Indeed, despite the absence of echocardiographic evidence of left heart dysfunction, 3 (9.1%) of our 33 patients who underwent RHC had postcapillary pulmonary hypertension.

It may be of interest to identify other variables that increase the suspicion of PAH development: age, type of SSc, and DLCO could be considered. Because the risk for development of PAH between patients with lcSSC and those with dcSSc can no longer be considered different, all SSc patients should be screened for PAH (22). It has been reported that a DLCO of <55% of predicted may be associated with future development of PAH (22). In our SSc population without severe lung disease, a low DLCO (<60%) was associated with a higher probability of PAH, but introducing this parameter into the model did not yield better performance for PAH detection. Furthermore, 5 (27.8%) of the 18 patients with newly diagnosed PAH had a DLCO of >60%. The longitudinal followup of these patients will provide us with some information on the clinical outcome of patients with a DLCO of <60% in whom PAH was not suspected according to our algorithm.

The primary purpose of a screening algorithm is early diagnosis. With our algorithm, combining symptoms (dyspnea not explained by another cause) and echographic parameters (VTR ≥2.5 meters/second), PAH was effectively detected at an early stage. Among the 33 patients who underwent RHC, PAH was confirmed in 18 and mPAP was ≥20 mm Hg in 6 others. Indeed, an mPAP of ≥20 mm Hg is abnormal and reflects mild pulmonary hypertension, as previously defined for other conditions, such as chronic obstructive pulmonary disease (15) or sleep-disordered breathing (16).

A recent consensus of experts confirmed that no clear guidelines that distinguish normal from pathologic PAP levels are available, and proposed that mild PAH should be suspected if Doppler echocardiography shows an sPAP of ∼36–50 mm Hg or a resting VTR of 2.8–3.4 meters/second (23). It is notable that if this threshold had been used in our study population, 6 patients would have been placed in this category, of whom 2 with mild PAH (mPAP of 25 and 27 mm Hg on RHC) would have been missed, and RHC would not have been performed in 1 patient with an mPAP at rest of 20 mm Hg. Although progress in the echocardiography techniques and in the correlation between RHC and echocardiography data is clearly needed, the present results show that our algorithm is currently a good compromise for PAH detection.

The relationship between higher mPAP during RHC and unfavorable outcome was demonstrated in a large, prospective, 4-year followup study (18). Patients with mPAP <32 mm Hg at the time of the first RHC had a 30% higher 1-year survival rate than patients with mPAP >45 mm Hg (93% versus 61%). This finding supports the need for aggressive strategies to identify SSc patients with PAH at an early stage. To date, the current evidence-based treatment algorithm, based on grading of evidence for efficacy from clinical studies and regulatory approval, addresses the population of patients with idiopathic PAH or patients with PAH associated with scleroderma or use of an anorexigen (27) who are in NYHA functional class III or IV. These patients are candidates for long-term therapy with oral dual endothelin receptor antagonist (bosentan) or prostanoids (epoprostenol, iloprost, or remodulin) (28, 29). Of our patients with newly diagnosed PAH, almost half were in NYHA functional class III or IV and met the criteria for initiation of therapy according to these current guidelines.

Our screening program led us to estimate a PAH frequency of 7.85% (95% CI 5.70–10.00) in our population, consistent with the 12% recently reported by Mukerjee et al (18). In the literature, the mean from several studies is 16% (300 of 1,837 patients) (22).

There are limitations to our study. Our screening algorithm relies on the quantification of VTR. As noted above, the reliability of the Doppler echocardiographic examination is pivotal, and the experience of the echocardiographer plays a role in the accurate determination of VTR. It is also important that echocardiographic procedures be standardized. In order to maximize the performance of echocardiography, new parameters have been proposed to estimate pulmonary hemodynamics, such as pulmonary regurgitant Doppler signals or pulmonary acceleration time (22, 23). However, guidelines do not provide any threshold for these new parameters. In the followup of our study cohort, these criteria will be used to assess the suspicion of PAH in patients in whom VTR cannot be quantified. In our study, most patients who underwent RHC were tested at rest only. Evaluation of pulmonary artery pressures during exercise is of interest for detection of an abnormal cardiopulmonary profile and should be encouraged, thus allowing for diagnosis of PAH at an early stage.

Since we excluded SSc patients with severe pulmonary function abnormalities, our conclusions cannot be extrapolated to the whole SSc population. It is known that SSc patients with severe interstitial lung involvement may develop pulmonary hypertension, which is generally not as severe as is found in those with PAH in the absence of fibrosis (22). However, there is a subgroup of patients who have a moderate amount of fibrosis and PAH that is out of proportion to the degree of fibrosis (22), which could warrant further investigation.

In conclusion, the purpose of our study was not to establish the optimal criteria and thresholds for screening SSc patients for PAH; however, we demonstrated that our screening algorithm, based on symptoms, Doppler echocardiographic evaluation of VTR, and RHC, can be applied in a multicenter setting or routine practice. Combining dyspnea (not explained by another cause) with a VTR threshold of 2.5 meters/second accurately identified a subgroup (9%) of high-risk patients, in whom PAH was confirmed by RHC in 55% and postcapillary pulmonary hypertension was identified in a further 10%. The prevalence of PAH in our study is consistent with recent reports. In addition, and as indicated by RHC data, systematic application of our screening algorithm to SSc patients allowed detection of mild PAH at an early stage. Whether such patients will develop severe PAH in all cases is not known; however, these patients already present with signs of right heart dysfunction, and almost half of them meet criteria for therapeutic intervention. It is unclear whether this early diagnosis and management algorithm will yield a better prognosis. This will be evaluated in the ongoing 3-year followup of this large SSc cohort.


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  2. Abstract
  • 1
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  1. Top of page
  2. Abstract

Members of the Itinerair-Scleroderma Investigators Group (all in France) are as follows: Loïc Guillevin, Jean-Marie Houeix, Luc Mouthon, Linda Nasciembeni (Bobigny, Avicenne); Virginie Bernard, Marc-Alain Billès, Marie-Sylvie Doutre, Claire Dromer, Stéphane Lafitte, Thierry Schaeverbeke, Jean-François Viallard (Bordeaux 1); Joël Constans, Philippe Gosse, Philippe Lemetayer (Bordeaux 2); Abdul Monem Hamid, Marc Humbert, Vincent Ioos, Xavier Jaïs, Gérald Simonneau, Olivier Sitbon (Clamart, Antoine-Béclère); Serge Adnot, Anne Cosnes, Pascal Guéret, Juliette Rousseau (Créteil, Henri-Mondor); Patrick Carpentier, Jean-Louis Cracowski, Christophe Pison (Grenoble); Joël Dagorn, Pascal de Groote, Eric Hachulla, Pierre-Yves Hatron, Marc Lambert, Nicolas Lamblin, David Launay, Viviane Queyrel (Lille); Jean-Yves Bayle, Michèle Bertocchi, Jean-François Cordier, Fadi Jamal, Jacques Ninet, Michel Ovize (Lyon); Sylvie Hesse-Bonerandi, Martine Reynaud-Gaubert, Gilbert Habib, Jean-Robert Harle, Sébastien Renard, Frédérique Retornaz (Marseille); François Chabot, Claude Schmidt, Jean-Luc Schmutz, Christine Suty-Selton (Nancy); Christian Agard, Erwan Bressolette, Alain Haloun, Mohamed Hamidou, Jean-Marc Langlard (Nantes); Eric Brochet, Olivier Lidove, Thomas Papo, Catherine Picard-Dahan, Dominique de Zuttere (Paris, Bichat); Yannick Allanore, Laure Cabanes, André Kahan, Christophe Meune, Christian Spaulding (Paris, Cochin); Camille Francès, Anne-Claude Koeger, Dominique de Zuttere (Paris, La Pitié–Salpêtrière); Jean Cabane, Ariel Cohen, Kiet Phong Tiev (Paris, Saint-Antoine); Yara Antakly-Hanon, Isabelle Lazareth, Ulrique Michon-Pasturel (Paris, Saint-Joseph); Dominique Farge, Suzanne Ménasché (Paris, Saint-Louis); Jacqueline Chevrant-Breton, Philippe Delaval, Patrice Jego, Marcel Laurent (Rennes); Fabrice Bauer, Geneviève Dérumeaux, Hélène Etchaninoff, Isabelle Marie (Rouen); Ari Chaouat, Jean-Louis Pasquali, Hélène Petit, Jean Sibilia (Strasbourg); Daniel Adoue, Daniel Conte, Bruno Degano (Toulouse); Véronique Eder, Elisabeth Diot, Christian Marchal, Laurent Machet, Olivier Marie, Frédéric Patat (Tours).