The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study)
Abstract
Objective
Most of the data about the prevalence of pulmonary arterial hypertension (PAH) are from tertiary centers that are biased toward seeing more severe cases; therefore, the true prevalence of PAH among patients with connective tissue disease is unknown. We sought to determine the point prevalence of undiagnosed PAH in community-based rheumatology practices.
Methods
The study design was a multicenter, prospective and retrospective survey and analysis of clinical cases in 50 community rheumatology practices. We evaluated a total of 909 patients with either scleroderma (systemic sclerosis [SSc]) or mixed connective tissue disease (MCTD). If a subject had not been diagnosed as having PAH, then a new Doppler echocardiogram was obtained to measure cardiac parameters, including estimated right ventricular systolic pressure (ERVSP), and a full review of medical records was done.
Results
Of 909 screened patients, 791 were evaluable and completed the study; 669 had not previously been studied for PAH. Of these 669 patients, 89 (13.3%) were found by Doppler echocardiography to have an ERVSP of ≥40 mm Hg. Of these 89 patients, 82 (92.1%) had SSc and 7 (7.9%) had MCTD. The total prevalence of PAH in the survey was 26.7% (211 of 791 patients, including 122 with known PAH and 89 newly diagnosed as having PAH). Doppler echocardiographic data showed 20 of 89 patients (22.5%) with ERVSP of ≥50 mm Hg, 20 of 89 patients (22.5%) with increased RV dimension, and 25 of 89 patients (28.1%) with right atrial enlargement. Patients with ERVSP ≥40 mm Hg had decreased exercise tolerance compared with those with ERVSP <40 mm Hg (27% compared with 9.5%, respectively, were severely symptomatic).
Conclusion
A significant number of patients with SSc or MCTD (13.3%) followed up in a community rheumatology practice setting have undiagnosed elevated ERVSP consistent with PAH.
Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with scleroderma (systemic sclerosis [SSc]) and mixed connective tissue disease (MCTD) (1-3), yet physicians often do not detect its presence until the late stages of disease. The reported range for the prevalence of PAH is 5–50% among SSc patients (4), while it has a prevalence of 25% in patients with MCTD and 20% in those with systemic lupus erythematosus (5). This wide range in the reported frequency of PAH is probably due to differences in the methods and criteria used to make a diagnosis, as well as to differences in the patient populations. Some studies rely solely on heart catheterization studies in selected patients, while others have used clinical and/or Doppler echocardiography criteria. Most of the data about the prevalence of PAH come from university or tertiary centers that are biased toward seeing severe disease; therefore, the true prevalence of PAH among patients with connective tissue disease is unknown. Recent surveys of cohorts of SSc patients at hospital-based or tertiary centers suggest that ∼12–28% of these patients have PAH (3, 6, 7).
The presence of PAH may be underdiagnosed, because awareness of the preclinical asymptomatic phase is low among physicians and because early symptoms are frequently attributed to the underlying connective tissue disease. PAH in SSc patients has an extremely poor prognosis, with a reported median survival of 12 months following diagnosis (2, 7-9). Most agree that the next challenge in managing patients with PAH is detection of the disease process at an early or presymptomatic stage with the goal of preventing or delaying disease progression.
While diagnosis of PAH by heart catheterization still remains the gold standard and is highly recommended before commencing therapy, Doppler echocardiography is the most practical and reliable noninvasive tool to survey for disease (10, 11). We sought to determine the point prevalence of undiagnosed PAH in community-based rheumatology practices by conducting a survey using Doppler echocardiography technology.
PATIENTS AND METHODS
Subjects.
Centers were eligible as community-based rheumatology practices if they were geographically and legally distinct from a tertiary, teaching rheumatology center. Investigators identified all of their living patients with SSc or MCTD who had visited the practice at least once in the previous 12 months. Patients had to be at least 18 years old and fulfill 1 of the following 3 conditions: 1) have disease meeting the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for SSc (12); 2) have at least 3 of 5 features of the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias); or 3) have a diagnosis of MCTD as defined by the Alarcon-Segovia and Cardiel criteria (13). Patients were excluded if they had a connective tissue disorder other than SSc or MCTD, sarcoidosis, human immunodeficiency virus, a history of congenital heart disease or left-sided heart failure, chronic thromboembolic pulmonary hypertension, or severe chronic obstructive pulmonary disease. The study was approved by the appropriate Institutional Review Boards.
Allocation to study groups and data collected.
At the time of chart review, if the patient had an existing diagnosis of PAH according to the current rheumatologist, this patient was allocated to the retrospective group, and any further data were obtained from the patient's existing medical record. If the patient did not have an existing diagnosis of PAH, he/she was allocated to the prospective group and invited to join the study. After informed consent was obtained, patients in the prospective group underwent Doppler echocardiography of the right and left chambers of the heart (unless one had been performed within the previous 6 months). They completed a questionnaire about dyspnea and were examined for the presence of digital ulcers. Additional clinical and serologic data were collected from the medical records.
Doppler echocardiography.
Each patient without an existing diagnosis of PAH (prospective group) underwent Doppler echocardiography if one had not been performed within the previous 6 months. The echocardiography was performed at a site of the investigator's choice, with a specific request for the ascertainment of estimated right ventricular systolic pressure (ERVSP) as measured by the peak tricuspid regurgitant flow velocity using the modified Bernoulli equation, P = 4v2, where P represents the pressure in mm Hg and v represents the maximal regurgitant velocity in meters per second. The addition of the estimated right atrial (RA) pressure was left to the discretion of the echocardiographer at the individual sites. If a tricuspid regurgitant flow was not adequately identified, the pressure was recorded as “indeterminate.” Evidence of right ventricular (RV) dysfunction was assessed by the following features: 1) increased RV dimension, defined as the RV diameter at the level of the tricuspid annulus being >4 cm in the 4-chamber view; 2) RA enlargement, defined as a space of >4 cm between the interatrial septum and the lateral RA wall; and 3) abnormal intraventricular septal motion in any view, defined by a thickening of the interventricular septum during systole, but with no movement toward the left ventricle (LV), or with septal motion toward the RV. We considered an ERVSP ≥40 mm Hg to be consistent with the presence of PAH.
Dyspnea questionnaire.
Each patient in the prospective group was asked to complete a dyspnea questionnaire rating the severity of dyspnea at a single time point. A score was calculated based on the rating for 3 different categories: functional impairment, magnitude of task, and magnitude of effort, with 5 grades of dyspnea per category (from 0 [severe] to 4 [unimpaired]). These categories were further simplified to classify patients with a dyspnea score of 4 as asymptomatic, those with grades 2 or 3 as mildly symptomatic, and those with grades 0 or 1 as severely symptomatic.
Statistical analysis.
The final population was used for all statistical analyses except for those involving demographics, which were derived from the population of evaluable patients. The goal of the primary analysis was to estimate the point prevalence of undiagnosed PAH, expressed as a simple proportion, in patients with SSc or MCTD who were attending community-based rheumatology clinics. Proportions were also used for the majority of the secondary analyses, and comparisons between groups were tested for differences using chi-square tests or Student's t-tests, in which P values less than 0.05 were considered to be significant.
Since there was a potential for selection bias, physicians were asked to obtain the medical records of their known patients with SSc or MCTD and to screen those patients for inclusion at the time of data entry into the Web-based electronic data capture system. In order to minimize excessive enrollment of patients from individual sites, a limit of 25 screened patients was allowed until the last 100 patients were required, at which time patient entry was allowed on a competitive basis. A proportion of sites were monitored for data verification.
Role of the funding source.
Actelion Pharmaceuticals US, Inc. funded this investigation. Employees of Actelion Pharmaceuticals participated in the design of the study, in the collection, analysis, and interpretation of the data, and in the decision to report the findings.
RESULTS
Centers.
Fifty sites (46 in the US and 4 in Canada) participated in the study, with an average of 18 patients per site (range 2–55). A list of investigators in the study (called the UNCOVER [The Prevalence of Undiagnosed Pulmonary Arterial Hypertension in Subjects with Connective Tissue Disease at the Secondary Health Care Level of Community-Based Rheumatologists] Study) is shown in Appendix A.
Patient populations (Table 1).
A total of 909 patients were screened, and 815 patients were considered evaluable in that they met the inclusion criteria and were not lost to followup. Of these 815 patients, 693 had no previous diagnosis of PAH (the prospective group), and 122 were known to have PAH (the retrospective group). Twenty-four patients in the prospective group did not undergo Doppler echocardiography, which left 669 patients (82.1% of the evaluable patients) with complete Doppler echocardiographic and questionnaire data. Of the 693 patients in the prospective group, only 190 (27.4%) had previously been evaluated for PAH, and only 78 (11.3%) had undergone Doppler echocardiography in the previous 6 months. The 2 centers with the highest levels of enrollment entered 55 and 51 patients. However, the ratio of the number of retrospectively studied patients to the number of prospectively studied patients in each of these 2 centers was similar to that in the group as a whole.
| Patients | Unknown PAH status | PAH present | Total |
|---|---|---|---|
| Evaluable | |||
| With SSc | 604 | 111 | 715 |
| With MCTD | 89 | 11 | 100 |
| Total | 693 | 122 | 815 |
| Final | |||
| With SSc | 586 | 111 | 697 |
| With MCTD | 83 | 11 | 94 |
| Total | 669 | 122 | 791 |
- * We originally screened a population of 909 patients. The evaluable population consisted of patients who passed the original screening and were not lost to followup. The final population consisted of the evaluable patients who underwent Doppler echocardiography and completed the dyspnea questionnaire. PAH = pulmonary arterial hypertension; SSc = systemic sclerosis; MCTD = mixed connective tissue disease.
Demographics.
In the population of 815 evaluable patients, 731 (89.7%) were women. The mean ± SD age of patients in the retrospective (n = 122) and prospective (n = 693) groups was 62.4 ± 13.0 years and 55.5 ± 13.1 years, respectively, and the mean ± SD time since disease onset was 8.5 ± 6.5 years and 7.8 ± 6.7 years, respectively. The mean ± SD time since the onset of Raynaud's phenomenon was 10.0 ± 7.9 years for the total population of 815 evaluable patients. SSc was diagnosed in 715 of the 815 evaluable patients (87.7%). Of the 693 patients in the prospective group, 604 were diagnosed as having SSc (38.1% of whom met the ACR criteria and 61.8% of whom met the criteria for the CREST syndrome). Of the 604 prospectively studied patients diagnosed as having SSc, 382 (63.2%) had limited disease, 220 (36.4%) had diffuse disease, and 2 were not classified. Of the total of 815 evaluable patients, 100 had MCTD (11 of 122 [9.0%] in the retrospective group and 89 of 693 [12.8%] in the prospective group).
Prevalence of PAH.
Doppler echocardiographic data were obtained on 669 of 693 patients in the prospective group because 24 patients did not complete the study. Eighty-nine of these 669 patients (13.3%) had evidence of PAH as defined by an ERVSP of ≥40 mm Hg. The total prevalence of PAH in the survey was 122 known cases in the retrospective group and 89 newly diagnosed cases (yielding 211 patients with PAH in a total of 791 patients with SSc or MCTD [26.7%] attending community-based rheumatology clinics). Of these 89 patients, 82 (92.1%) had SSc and 7 (7.9%) had MCTD.
Echocardiographic findings.
In the final prospective group, 282 of 669 patients (42.2%) had an ERVSP ≥30 mm Hg (Table 2). Twenty of 669 patients (3.0%) had an ERVSP ≥50 mm Hg. Of the 669 patients in the final prospective group, 127 (19.0%) had echocardiograms that could not be used to evaluate ERVSP, since the tricuspid regurgitant flow could not be identified on Doppler echocardiography. For purposes of comparison, echocardiography findings among 453 patients in the prospective group with an ERVSP <40 mm Hg and 89 with an ERVSP ≥40 mm Hg, respectively, showed increases in the following parameters with increasing ERVSP values: RV dimension (61 of 453 patients [13.5%] versus 20 of 89 patients [22.5%]; P = 0.03), RA enlargement (43 of 453 patients [9.5%] versus 25 of 89 patients [28.1%]; P < 0.0001), abnormal septal motion (11 of 453 patients [2.4%] versus 3 of 89 patients [3.4%]; P = 0.61), and ≥1 aspect of RV dysfunction (85 of 453 patients [18.8%] versus 34 of 89 patients [38.2%]; P < 0.0001). There was no difference between patients with ERVSP <40 mm Hg and those with ERVSP ≥40 mm Hg in the mean ± SD LV ejection fractions (63.0 ± 8.3% and 61.8 ± 10.8%, respectively), LV end-diastolic dimension (4.4 ± 0.6 cm3 and 4.5 ± 0.6 cm3, respectively), and LV wall thickness (10.6 ± 1.9 mm and 9.6 ± 1.9 mm, respectively).
| ERVSP, mm Hg | No. (%) of patients |
|---|---|
| ≥30 | 282 (42.2) |
| ≥35 | 158 (23.6) |
| ≥40 | 89 (13.3) |
| ≥45 | 45 (6.7) |
| ≥50 | 20 (3.0) |
| ≥60 | 6 (0.9) |
- * ERVSP = estimated right ventricular systolic pressure; PAH = pulmonary arterial hypertension.
Retrospectively studied patients.
Of the 122 patients with a preexisting diagnosis of PAH, 111 had SSc and 11 had MCTD. The diagnosis of PAH in the retrospectively studied group was “as defined by the investigator,” the rheumatologist's opinion. One hundred fifteen patients (94.3%) were diagnosed as having PAH by Doppler echocardiography, and only 7 (5.7%) were diagnosed by right heart catheterization. Of the 115 patients diagnosed by Doppler echocardiography, only 14 (12.2%) underwent right heart catheterization following the echocardiography, yielding a total of 21 of 122 patients (17.2%) diagnosed as having PAH who had undergone a confirmatory right heart catheterization. Conversely, 101 of 122 patients (82.8%) had been diagnosed as having PAH by Doppler echocardiography without undergoing a confirmatory right heart catheterization. Of the 115 patients diagnosed by Doppler echocardiography, 13 (11.3%) had ERVSP <35 mm Hg, 25 (21.7%) had ERVSP <40 mm Hg, and 90 (78.3%) had ERVSP ≥40 mm Hg.
Of the 122 patients with PAH, only 51 (41.8%) were receiving specific treatment for PAH. Of these 51 patients, 36 (70.6%) were receiving bosentan, 5 (9.8%) were receiving epoprostenol, and 10 (19.6%) were receiving other types of treatment for PAH.
Dyspnea.
Of the 693 patients in the prospective group, 686 (99.0%) completed the dyspnea questionnaire, while 669 (96.5%) completed both the questionnaire and the prospective Doppler echocardiography study. Of the 89 patients with an ERVSP ≥40 mm Hg, 76 (85%) demonstrated either mild or severe functional impairment compared with 320 of the 580 patients with ERVSP <40 mm Hg (55%) (Figure 1). Compared with patients with an ERVSP <40 mm Hg, a larger proportion of patients with an ERVSP ≥40 mm Hg also had impairments in magnitude of task and effort.
Relationship of dyspnea to estimated right ventricular systolic pressure (ERVSP). Each of the 669 patients without an existing diagnosis of pulmonary arterial hypertension (the prospective group) was asked to complete a questionnaire rating the severity of dyspnea at a single time point. A grade was calculated based on the rating for 3 different categories (functional impairment, magnitude of task, and magnitude of effort), with 5 grades of dyspnea per category (0 or 1 = severely symptomatic; 2 or 3 = mildly symptomatic; 4 = asymptomatic). Lower scores indicated greater levels of dyspnea. Values are the percentage of patients with a given grade of dyspnea for each category, dichotomized by ERVSP (<40 mm Hg or ≥40 mm Hg).
Digital ulcers.
Among all patients (retrospectively plus prospectively studied patients), there was no association between having a history of digital ulcers and the presence of PAH as defined by an ERVSP of ≥40 mm Hg (79 patients with PAH of 270 patients with ulcers [29.3%] versus 132 patients with PAH of 521 patients without ulcers [25.3%]; P = 0.237 by chi-square test).
Pulmonary function tests (PFTs).
Among all 791 patients, results of PFTs were reported for 401, of whom 86 of 122 patients (70.5%) were in the retrospective group and 315 of 669 patients (47.1%) were in the prospective group. Only 29 of 89 patients (32.6%) in the prospective group with ERVSP ≥40 mm Hg had PFT results available for review. In the prospective group, the percent predicted diffusing capacity for carbon monoxide (DLCO) was significantly lower in patients with ERVSP ≥40 mm Hg than in patients with ERVSP <40 mm Hg (58.9 ± 24.1% versus 71.9 ± 19.7%; P = 0.005 by t-test) (Table 3). In the entire population (retrospectively plus prospectively studied patients) for whom results of PFTs were available, the DLCO was significantly lower in patients with ERVSP ≥40 mm Hg (Table 4). It should be pointed out that in the prospective group, 47 of 141 patients (33.3%) with no impairment according to the dyspnea questionnaire had PFT results available for review compared with 268 of 528 patients (50.8%) with moderate or severe impairment (P = 0.0002), indicating that patients with dyspnea were more likely to have been sent for PFTs.
| PFT result | ERVSP ≥40 mm Hg (n = 29) | ERVSP <40 mm Hg (n = 286) | P |
|---|---|---|---|
| TLC | 4.3 | 4.6 | 0.18 |
| TLC, % predicted | 93.1 | 88.5 | 0.36 |
| DLCO uncorrected | 12.6 | 16.8 | 0.0008 |
| DLCO uncorrected, % predicted | 58.9 | 71.9 | 0.005 |
| DLCO corrected | 11.0 | 13.9 | 0.13 |
| DLCO corrected, % predicted | 67.3 | 76.2 | 0.10 |
| FVC | 2.4 | 3.0 | <0.0001 |
| FVC, % predicted | 82.9 | 88.2 | 0.13 |
- * PFTs = pulmonary function tests; ERVSP = estimated right ventricular systolic pressure; TLC = total lung capacity (in liters); DLCO = diffusing capacity for carbon monoxide (in ml/minute/mm Hg); DLCO corrected = DLCO corrected for hemoglobin; FVC = forced vital capacity (in liters).
| PFT result | ERVSP ≥40 mm Hg (n = 115) | ERVSP <40 mm Hg (n = 286) | P |
|---|---|---|---|
| TLC, % predicted | |||
| ≤80 | 49 (52.1) | 64 (28.1) | <0.0001 |
| >80 | 45 (47.9) | 164 (71.9) | |
| DLCO corrected, % predicted | |||
| ≤80 | 61 (81.3) | 123 (53.9) | <0.0001 |
| >80 | 14 (18.7) | 105 (46.1) | |
| FVC, % predicted | |||
| ≤80 | 62 (56.4) | 86 (30.6) | <0.0001 |
| >80 | 48 (43.6) | 195 (69.4) |
- * Values are the number (%) of patients for whom results were available on the given PFT (predicted TLC, predicted DLCO corrected, or predicted FVC). Retrospective group = subjects in survey with known pulmonary arterial hypertension (PAH); prospective group = subjects in survey with unknown PAH status (see Table 3 for other definitions).
Serology.
A positive antinuclear antibody titer was found in 615 of the 669 evaluable patients in the prospective group (91.9%). Of these 615 patients, anticentromere antibodies (ACAs) were found in 197 (32%), antitopoisomerase antibodies were found in 38 (6.2%), and anti–U1 RNP was found in 100 (16.3%). There was no association of any of these antibodies (either antibody positivity or antibody negativity) with the presence of PAH or with ERVSP ≥40 mm Hg.
DISCUSSION
The main finding in this study is that a significant number (point prevalence 13.3%) of patients with SSc and MCTD followed up in 50 different community-based rheumatology practices had an undiagnosed elevated ERVSP, as measured by Doppler echocardiography, consistent with PAH. The prevalence of these Doppler echocardiographic abnormalities in the present study is similar to those found in surveys of patients followed up in hospital-based or tertiary centers, and until now it was suspected that those prevalences were inflated by referral bias (3, 6, 7). In addition, 22.5% of the 89 patients with ERVSP ≥40 mm Hg had a very high estimated pressure of ≥50 mm Hg; 22.5% had an increase in RV dimension and 28.1% had RA enlargement, which are suggestive of advanced disease. We also found that patients with ERVSP ≥40 mm Hg had a decreased exercise tolerance compared with those whose pressure was <40 mm Hg. These data indicate that significant numbers of both asymptomatic and symptomatic patients with SSc or MCTD in a community rheumatology practice have undiagnosed PAH.
While it is well established that there is an increased risk of pulmonary hypertension associated with connective tissue disease, especially SSc and MCTD, this is the first attempt to define the prevalence of unrecognized cases in a community setting, where one might expect a milder disease case mix. The importance of this finding is emphasized by studies demonstrating a substantial increased mortality risk associated with the development of PAH in patients with SSc and other connective tissue diseases (2, 3, 8, 9). MacGregor et al report that a single Doppler echocardiographic pressure reading of ≥30 mm Hg is associated with a 20% mortality rate in 20 months (9). Similarly, it is reported that the survival rates in SSc are 81%, 63%, and 56% at 1, 2, and 3 years, respectively, after the diagnosis of PAH (3). Among patients with SSc, the retrospective mortality risk ratios (relative to patients without lung disease) were 2.9, 2.4, and 1.6 for patients with isolated PAH, restrictive lung disease combined with PAH, and restrictive lung disease alone, respectively (7). In a survey of serial Doppler echocardiographic studies in 282 SSc patients, it was reported that an increase of 10–20 mm Hg in the ERVSP from the previous study was associated with an increased risk of death within 7–8 months (14). This suggests that Doppler echocardiographic findings compatible with PAH in SSc patients, even without confirmatory heart catheterization data, are a risk factor for poor survival.
The other reason detection of PAH is important is that we now have therapeutic options that improve quality of life and exercise capacity in patients with class III and class IV functional status (15-17). However, it is not yet clear whether therapy improves survival in SSc patients with advanced PAH. Kuhn et al report that among 91 patients with PAH who were treated with epoprostenol, survival was poor in SSc patients (hazard ratio 2.32, 95% confidence interval 1.08–4.99) compared with that in patients with other forms of PAH, including those with primary pulmonary hypertension and congenital heart disease (18). The challenge for the future is to determine whether early diagnosis and intervention will prevent progression to advanced disease that is irreversible or difficult to treat.
Previous estimates of the prevalence of PAH among patients with SSc or other connective tissue disease vary widely, ranging from 5% to 50% (4). In a Canadian prospective study, only 4.9% of SSc patients were diagnosed as having PAH using Doppler echocardiography (2). Similar surveys in the UK found prevalences of 13% and 12% (3, 9), and surveys in the US found prevalences of 35% and 38.6% (19, 20). This variation is probably due to differences in the definition of PAH and in the populations of patients studied. Patients with mild or moderate PAH often exhibit no or nonspecific symptoms, or they may only have minimal shortness of breath on exertion. Physical findings may be absent in early disease, and chest radiographs are usually nondiagnostic. There are risk factors that should make the physician more suspicious of the presence of PAH, including a diagnosis of connective tissue disease (especially limited SSc), a late age at onset of SSc (20), progressive decline in the DLCO in SSc (21), and the presence of certain autoantibodies, including ACAs, anti-B23, anti–U3 RNP, anti–U1 RNP, or anti-Th/To antibodies (4). Rapidly progressive PAH presents more often as isolated PAH in patients with limited SSc (9).
Doppler echocardiography has emerged as a reliable means of assessing pulmonary pressure (ERVSP) noninvasively, as illustrated in this study. This method yields values that correlate well with those obtained using right heart catheterization (10, 22), and it is currently the most commonly used screening tool for PAH. We recognize that patients with PAH defined by Doppler echocardiography may have normal values at the time of right heart catheterization; for that reason, we chose a conservative definition of a reading of ≥40 mm Hg. In fact, we found that more than 20% of our patients with unrecognized PAH had pressures ≥50 mm Hg, and, despite the presence of symptoms in many of these patients, previous investigations to diagnose PAH were lacking. In fact, only 27% of the patients with unknown PAH status had ever been evaluated for PAH prior to the present study.
Doppler echocardiography and PFTs appear to perform adequately for identifying patients with advanced PAH, but there are very few data showing the reliability of these techniques in patients without clinical symptoms. Mukerjee et al recently reported findings of a prospective study designed for early identification of SSc-related PAH through the use of Doppler echocardiography and DLCO, and they compared these data with those obtained from cardiac catheterization (23). ERVSP by Doppler echocardiography showed a moderate positive correlation (r2 = 0.44, P < 0.005) with both mean pulmonary artery pressure and invasively determined tricuspid gradient (23). In their study, 97% of patients with a Doppler echocardiographic finding of ERVSP ≥45 mm Hg were found to have PAH at catheterization. A Doppler echocardiographic threshold of <40 mm Hg versus ≥40 mm Hg had a positive predictive value of 92% and a negative predictive value of 44% (23). Therefore, as an adjunct to clinical evaluation, Doppler echocardiography is a reasonable screening approach for identifying patients with PAH.
Methodologic considerations include the fact that 2 of our centers enrolled more patients than the others; however, the ratio of the number of retrospectively studied patients to the number of prospectively studied patients in each of these 2 centers was similar to that in the overall study, indicating the likely absence of selection bias. Another potential bias could have been introduced by the study design, in that participating rheumatologists were aware of the goal to discover patients who might have PAH. However, they were asked to survey all patients diagnosed as having SSc or MCTD in their practices who were being actively followed up (seen within the previous 12 months). Interestingly, we found that the majority of patients who had not been diagnosed as having PAH (503 of 693 [72.6%]) had not been studied for PAH in the past.
We did not use a central laboratory to perform or evaluate all the Doppler echocardiography studies, but we did use predefined criteria to guide the interpretation of the results. Investigators at each individual site estimated the RVSP using the Bernoulli equation with the addition of the estimated RA pressure according to their standard laboratory criteria. Right heart catheterization was used in only a small minority of patients, either as the primary diagnostic or confirmatory tool; these findings suggest the need for a lower threshold of referral to cardiologists or pulmonologists.
It is reported that digital ulcers are more common among SSc patients with PAH than among those without PAH (6, 21). We did not confirm this finding, in that our patients with or without PAH had a similar history of digital ulcers. We did find an association between a reduced DLCO and the presence of PAH defined by Doppler echocardiography, as reported by others (1, 21). However, Mukerjee et al found a weak correlation of DLCO with mean pulmonary artery pressure by heart catheterization. They suggest that the positive predictive accuracy of currently used noninvasive tests is adequate for the diagnosis of PAH, provided that sufficiently high thresholds are used (23). However, for those individuals with a mixed clinical picture who may have LV dysfunction, particularly diastolic dysfunction, direct measurements of pulmonary pressure and wedge pressures remain the gold standard.
In summary, this study is the first to address the prevalence of PAH in a community-based rheumatology practice setting. Using accepted Doppler echocardiography technology as a screening tool, we found that a significant number (13.3%) of SSc and MCTD patients from 50 different community-based practices had undiagnosed PAH. Many of these patients had Doppler echocardiographic evidence of RV dysfunction, an abnormally low DLCO, and decreased exercise tolerance suggestive of advanced disease. These data suggest that Doppler echocardiographic evaluation of SSc and MCTD patients followed up in the community is justified, irrespective of symptoms, to detect patients who may need further evaluation, close surveillance, and/or intervention for underlying PAH. These findings further support the recommendation of the American College of Chest Physicians' Evidence-Based Clinical Practice Guidelines that for asymptomatic patients at high risk for PAH, Doppler echocardiography should be performed to detect elevated pulmonary arterial pressure (24).
Acknowledgements
We would like to thank CRNets for the setup of the Web-based electronic data capture system and Dimensional Healthcare for managing aspects of the logistics of the study. We would also like to thank Huey Ju (ICON Clinical Research) for performing the statistical analyses, Lori Gutierrez (Actelion Pharmaceuticals) for the tables and graphs, and Valerie Dukes for preparation of the manuscript.
APPENDIX A
UNCOVER STUDY INVESTIGATORS
Investigators in the UNCOVER Study are as follows: Julio Aponte, MD (Cleveland, OH), Steven Baak, MD (Florissant, MO), Philip A. Baer, MD (Scarborough, ON, Canada), Neal Birnbaum, MD (San Francisco, CA), Howard Busch, MD (Jupiter, FL), David Campbell, MD (Fort Wayne, IN), John Condemi, MD (Rochester, NY), Mary Ellen Csuka, MD (Milwaukee, WI), Alfred Denio, MD (Virginia Beach, VA), Deborah Desir, MD (Hamden, CT), Justus Fiechtner, MD (Lansing, MI), John A. Goldman, MD (Atlanta, GA), Robert Griffin, MD (Reading, PA), Michael Gross, MD (Fair Lawn, NJ), Howard Hauptman, MD (Baltimore, MD), John A. Howland, MD (Bay City, MI), Joe Huffstutter, MD (Chattanooga, IN), Thomas Ignaczak, MD (Battle Creek, MI), Richard Jones, MD (Tuscaloosa, AL), Gurjit S. Kaeley, MD (Lakewood, WA), Albert R. Katz, MD (Tarzana, CA), Steven Ko, MD (Fort Wayne, IN), Steven Lauter, MD (St. Louis, MO), Sharon LeClercq, MD (Edmonton, Alberta, Canada), Wonil Lee, MD (North Hollywood, CA), Angela McCain, MD (Sugar Land, TX), David McLain, MD (Birmingham, AL), Carter Multz, MD (San Jose, CA), Frederick Murphy, MD (Duncansville, PA), Gary Myerson, MD (Atlanta, GA), Michael Neuwelt, MD (San Leandro, CA), Aileen Pangan, MD (Maywood, IL), Glenn Parris, MD (Lawrenceville, GA), Jeffrey Poiley, MD (Orlando, FL), Naveen Raja, MD (Whittier, CA), Daniel H. Rosler, MD (Milwaukee, WI), Alberto Santos-Ocampo, MD (Honolulu, HI), Brian Sayers, MD (Austin, TX), Gregory Schimizzi, MD (Wilmington, NC), William Shergy, MD (Huntsville, AL), Yvonne Sherrer, MD (Ft. Lauderdale, FL), Douglas Smith, MD (Indianapolis, IN), Neil I. Stahl, MD (Burke, VA), Evelyn Sutton, MD (Halifax, Nova Scotia, Canada), Timothy Swartz, MD (Kalamazoo, MI), Peter Valen, MD (La Crosse, WI), Daniel Wallace, MD (Los Angeles, CA), Jay Warrick, MD (Knoxville, TN), Francis M. Williams, MD (Houston, TX), Michel Zummer, MD (Montreal, QC, Canada).
