Rheumatology 2001; 40: 453-459
© 2001 British Society for Rheumatology
Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival
Departments of Rheumatology and Cardiology, Royal Free Hospital, Pond Street, London NW3 2QG, UK
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Abstract |
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Objective. To assess the rate of progression of pulmonary hypertension (PHT) in systemic sclerosis (SSc) and its bearing on mortality.
Methods. A retrospective record review of 930 patients with SSc attending a specialist centre was carried out. Those at risk for both idiopathic and secondary PHT were assessed by serial Doppler echocardiography. Mortality data were reviewed.
Results. The cumulative prevalence of PHT was 13%. Pressures remained static in most cases. The mortality among those with a single pressure reading of 30 mmHg or higher was 20% at 20 months. An increased mortality risk was associated with high initial pressures and rising pressures. Rapid pressure rises occurred more frequently in limited than in diffuse SSc.
Conclusions. The prevalence of PHT in SSc is high and the detection of PHT at any time in the disease course is associated with substantial mortality. These results demonstrate the value of echocardiographic screening for PHT in all patients with SSc.
KEY WORDS: Systemic sclerosis, Echocardiography, Vascular, Morbidity, Mortality.
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Introduction |
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Pulmonary hypertension (PHT) is widely recognized as an important complication of both limited and diffuse systemic sclerosis (SSc). When severe and established, it is difficult to treat and is associated with high mortality [1]. The awareness that this complication exhibits few symptoms or outward clinical signs until it is at a stage when it is life-threatening has alerted those managing patients with SSc to the need for screening for PHT early in the disease course [2]. There have, however, been few studies of PHT at earlier stages of its development and the clinical consequences of its early detection have not been well established. The recent study by Badesch et al. [3] shows that, for advanced disease, continuous ambulatory epoprostenol is effective both in terms of symptom relief and in improving exercise capacity in SSc-associated PHT. Warfarin is believed to improve survival in all patients with PHT [4, 5], and many new therapies are currently being evaluated (e.g. inhaled Iloprost, UT15, endothelin antagonist therapy). However, the place of treatment in SSc-associated PHT at all stages of the disease and in asymptomatic patients can only be fully assessed with knowledge of the natural history of this condition.
One of the practical difficulties in obtaining accurate data on pulmonary artery pressure has been the need for right heart catheterization. With advances in Doppler echocardiography in the last decade, reliable information on pulmonary artery pressure and right ventricular function can now be obtained non-invasively [6–8]. Over the last 8 yr, this technique has been carried out by our group at the Royal Free Hospital (RFH), London, in a large cohort of patients with both limited and diffuse disease attending for regular clinical assessments. Their clinical outcome and mortality has been documented carefully. The aim of this analysis was to review these data retrospectively to assess the natural history and progression of PHT in limited and diffuse SSc.
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Subjects and methods |
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Setting
This analysis used data gathered during routine clinical practice from in- and out-patients attending the RFH Connective Tissue Diseases Unit, a primary, secondary and tertiary referral centre for SSc. The patients attending the unit comprise local residents and referrals from throughout the UK and present at all stages in the disease course. The observations included in this study relate to the period between July 1992 and July 1997.
Patient selection and evaluation
All patients attending the unit completed a standardized interview and examination by a clinician. More detailed investigation of internal organ involvement was directed by clinical symptoms and signs, as part of normal clinical practice. The follow-up interval was determined by clinical need.
At the start of the period to which these observations relate, Doppler echocardiography was carried out in all patients for whom there was a clinical suspicion of PHT based on (i) the results of clinical examination, (ii) pulmonary function testing, (iii) plain chest radiography or (iv) thin-section high-resolution computed tomography (HRCT) (see definitions below). Follow-up clinical assessment, including repeat Doppler measurements and pulmonary function, was arranged annually, with more frequent assessment if there was clinical evidence of deterioration. With time, however, the high prevalence of mild PHT early in the disease course was recognized, and our practice changed to screen all patients with SSc attending for review for PHT irrespective of their symptoms and signs, with review examinations arranged at least annually.
Deaths during follow-up were identified by a routine questionnaire sent to general practitioners of patients and by screening death certification records. Information from these sources was reviewed by clinicians at RFH to allocate the principal cause of death. Where possible this was assigned as PHT-related or PHT-non-related.
Assessment of PHT
Echocardiograms were recorded with the patient in the left lateral decubitus position using a Vingmed CFM800 machine (Horton, Norway). Tricuspid regurgitant flow was identified by colour flow, pulse and continuous Doppler. The instantaneous drop in pressure from the right ventricle to the atrium was calculated for the highest Doppler signal velocity from the tricuspid regurgitant jet by the simplified Bernoulli equation. The sensitivity of Doppler echocardiography for detecting pulmonary artery systolic pressure (PASP) of 
30 mmHg, as defined by right heart catheterization, has been shown in a previous study of these patients to be 90% [7]. In the presence of tricuspid regurgitation, the correlation between measures of PASP on echocardiography and right heart catheterization was 0.83.
The examinations followed the usual clinical practice at RFH and were not all carried out by the same echocardiographer. All echocardiographers had been trained by a senior cardiologist (JD) and the methods of establishing pulmonary artery pressure were standardized. Any study that was technically difficult was reviewed and repeated by JD.
Definitions
For the purpose of this analysis, a PASP of 30 mmHg on Doppler echocardiography was taken as indicative of PHT [9]. Where possible, this pressure was considered as a continuous variable, but for some analyses PASP was considered to be low or high depending on whether it was below or above 60 mmHg. Patients were classified retrospectively as either having or being at risk of secondary PHT (sPHT) if at baseline or at any time during follow-up there was evidence of pulmonary fibrosis indicated by (i) a total lung capacity of 
70% of the predicted value; or (ii) an HRCT scan providing evidence of diffuse interstitial fibrosis or alveolitis (this was performed routinely in all patients with a total lung capacity between 70 and 80% of predicted); or (iii) FEV/FVC ratio 50%. In the absence of these findings at any stage during follow-up, patients were classified as either having or being at risk of isolated PHT (iPHT). SSc was classified as limited or diffuse depending on the extent of skin involvement at the end of the follow-up period [10].
Data analysis
The main aim of the analysis was to examine the progression of PASP with time and to assess the associated mortality risk. Assessing progression was complicated by the fact that individuals' measured PASP fluctuated between assessments, with measured pressures increasing as well as decreasing with time. Furthermore, the total number of follow-up echocardiographs, intervals between assessments and the length of follow-up varied. Overall, however, individual patients showed a consistent trend in their measurements over time. To analyse progression we used the slope (ß) of the linear regression of each subject's measurement on time as an appropriate summary measure representing the rate of change [11]. Where PASP was not recorded on echocardiography, the observations were treated as missing. For analysis, the distribution of ß was split into tertiles and the effect of baseline clinical variables on the tendency to progress was examined by logistic regression [12].
Mortality risk was assessed in patients who at any time during follow-up had a pressure recorded as 30 mmHg. The start of the follow-up interval was defined as the time at which patients were first recorded as having a pressure of 30 mmHg. Survival time was measured as the interval that elapsed until the recorded date of death, or, if the patient survived, the interval to 1 July 1997, which was defined as the end of the follow-up period. The effect of baseline variables on the rate of rise of PASP was examined by Cox proportional hazards modelling [12]. Multiple regression analysis was used to explore the confounding effects of age, sex, disease duration and disease subset. All analyses were carried out using the statistical software Stata (release 5.0; Stata Corporation, College Station, TX, USA).
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Results |
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Characteristics of the sample
During the period of this study, 295 patients with diffuse SSc (dSSc) and 635 patients with limited SSc (lSSc) attended for assessment. A total of 152 patients (112 with lSSc and 40 with dSSc) had Doppler echocardiograph assessments. On subsequent classification, 95 were classified as either having or being at risk of iPHT and 57 at risk of sPHT. Their characteristics are shown in Table 1
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The baseline echocardiographic assessments of these 152 patients are illustrated in the first column of Fig. 1
. In the iPHT group, 57 (60%) had an undetectable PASP at their first echocardiogram, 27 (29%) had a PASP between 30 and 60 mmHg, and 11 (12%) had a PASP of 60 mmHg. In the sPHT group, 20 (35%) had an undetectable PASP, 29 (51%) had a PASP between 30 and 60 mmHg and 8 (14%) had a PASP >60 mmHg.
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Progression of PHT
A summary of the results of the serial Doppler echocardiograph assessments is shown in Fig. 1
. The shading of each square represents the mean of recordings taken in a fixed 6-month interval. Pressures indicative of PHT are divided into two bands: a lower band of 30–60 mmHg and an upper band of >60 mmHg.
With continuing follow-up, most patients with clinically suspected PHT had the diagnosis subsequently confirmed by echocardiography. Of the sample of 152 patients who underwent baseline echocardiographs, 119 were documented as having PHT at any time during follow-up, as evidenced by a PASP recording of 30 mmHg on at least one occasion. These comprised 62 patients (55 with lSSc and 7 with dSSc) from the group classified as at risk of iPHT and 57 in the sPHT group (30 with lSSc and 27 with dSSc). These figures are equivalent to a cumulative prevalence for PHT of 13% for the group as a whole, with an equal prevalence in those with lSSc and dSSc.
Figure 1 shows that there was considerable fluctuation in PASP measurements during follow-up in both groups. Among those with documented PHT, the majority remained static within their pressure band or rose progressively. A smaller number showed falling pressures during follow-up, with some rising subsequently.
The transitions in pressure over follow-up are further illustrated in Table 2, which shows a snapshot of the data from baseline to 2 yr in 42 patients with iPHT and 30 with sPHT for whom the outcome between 2 and 3 yr is known. The table illustrates that one-third of patients suspected as having iPHT and one-half of patients suspected as having sPHT will have their diagnosis confirmed on echocardiography after 2 yr. Only one patient with iPHT progressed from the lower to the upper band of PASP during follow-up; the PASP of the others in this group either remained static or became so low as to be unrecordable. In the sPHT group, two patients' pressures fell from the upper to the lower band.
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The rate of pressure change with time was investigated further by examining the slope of the regression of PASP on time (ß). Unrecordable pressures were treated as missing values in assessing each ß. Hence this analysis relates only to the interval after patients were classified as having established PHT and was carried out only in those with subsequent abnormal pressure readings. Data were available for this analysis from 47 patients with iPHT and 36 with sPHT; the characteristics of these patients did not differ significantly from those listed in Table 1
. Three tertiles of the range of ß were defined. The median values of the annual pressure change for each tertile were as follows: -6.3 mmHg (lowest tertile; falling pressure); +1.2 mmHg (middle tertile; static pressure); and +12.1 mmHg (upper tertile; rising pressure).
The influence of baseline variables on the risk of rising vs static or falling PASP is shown in Table 3. The analysis shows that patients with limited as opposed to diffuse SSc were at substantially increased risk of progressing rapidly (only one of the patients with dSSc progressed rapidly). By contrast, a similar risk of rapid progression was seen in patients classified as iPHT and sPHT. Increasing age and the male sex were associated with an increased risk of rapid progression, although the confidence intervals around these estimates were wide and included unity. In multiple regression analyses, these observations for lSSc, older ages and males appeared to be independent of each other, and additionally were not influenced by disease duration.
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Mortality
A total of 18 deaths occurred during the follow-up period, 11 in the iPHT group (all of whom had lSSc) and seven in the sPHT group (three with dSSc and four with lSSc). Their disease characteristics and causes of death are listed in Table 4. In a total of six patients, death could be attributed directly to PHT. Cardiac causes accounted for death in five other patients and pulmonary causes (pulmonary fibrosis and pneumonia) in three. Figure 2 shows the Kaplan–Meier plot from life-table analysis of this data. The figure illustrates that 20% of the group are at risk of dying within 20 months of PHT first being detected on echo-Doppler. Proportional hazards regression modelling (Table 5) showed that there was a trend towards an increased risk of dying in males, in patients over the age of 50 yr, in patients with iPHT compared with sPHT, and in limited as opposed to diffuse disease. Significantly increased mortality was seen in those with a higher initial PASP, an effect that on multiple regression analyses was independent of age, sex, disease duration or disease subset. There was a trend to increasing mortality in those with rising compared with static and falling PASP during follow-up.
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Discussion |
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This analysis confirms that PHT is a common complication of both diffuse and limited SSc, with a cumulative prevalence of 13% during the follow-up interval of this study. In most patients with PHT, PASP remained static during follow-up and in almost a third of those assessed the mean level fell. Despite this, patients who had a single measurement of PASP of 30 mmHg or more were seen to have a risk of death of 20% at 20 months. The mortality risk is especially high in patients with high pressure at initial presentation and those with rising pressure during follow-up. Rapid rises were seen more frequently in males, among older subjects and in those with limited SSc.
This analysis was motivated by a need to review our own clinical practice in the assessment and management of PHT in SSc. We have been using Doppler echocardiography at the RFH for the non-invasive assessment of PASP in patients with SSc perceived to be at risk of pulmonary hypertension since the early 1990s. There was a need to appraise whether the prevalence and incidence of the disease in our patients justified regular screening examinations. It was also important to assess whether this practice provided prognostic information that would be of value both for patients and for directing the timing of specific treatment interventions such as the use of i.v. Iloprost.
Published data relating to this clinical setting are difficult to interpret. The precise prevalence of PHT in SSc is hard to evaluate accurately. Methods of subject selection vary and different methods have been used to establish the diagnosis. Autopsy and clinical series published in the 1960s and 1970s suggested a prevalence of over 60% [13, 14]. Estimates from prospective studies have been lower. Ungerer et al. [15], in a study conducted between 1973 and 1979, carried out extensive investigations, including cardiac catheterization, in 49 patients attending the UCLA (University of California at Los Angeles) scleroderma clinic. PHT was identified in 33% of the group overall and in 50% of those with limited disease. More recently, Stupi et al. [16] reported the results of studies conducted in 673 patients with limited SSc seen between 1963 and 1983 at the University of Pittsburgh. Patients had been screened for evidence of PHT by clinical examination and electrocardiography and the diagnosis confirmed by cardiac catheterization. Convincing clinical evidence of either isolated or secondary PHT was found in 9%.
Methods based on the use of clinical examination and electrocardiography are insensitive in the detection of early stages of PHT. These cases may be better detected by identifying an isolated reduction in pulmonary diffusing capacity or detecting the presence of PHT on Doppler echocardiography. In a series of studies published from the Pittsburgh Scleroderma Databank, the prevalence of isolated reduction in pulmonary diffusing capacity was estimated as between 10 and 19% [16–18]. In these studies, approximately half the cases were confirmed to have PHT on cardiac catheterization. These figures are consistent with our own estimates. Echo-Doppler examination has been used to assess the prevalence of PHT in three studies. Morelli et al. [19], in a study of 31 patients with SSc, found a prevalence of PHT of 43% among patients with lSSc and 52% in those with dSSc. Murata et al. [20] examined 71 patients with SSc and found a prevalence of 35%. Battle et al. [21] found a prevalence of PHT (defined as a pressure of 30 mmHg) of 34% in a mixed group of 34 patients with SSc and other connective tissue diseases. All these studies were clinic-based and the high prevalence figures relative to our own are likely to reflect differences in case selection.
Pulmonary diseases, in particular PHT, are recognized to account for the majority of deaths in SSc [22, 23]. However, published data on outcome relate in the main to severe and established disease. Koh et al. [24] demonstrated that severe PHT (confirmed by Doppler echocardiography and cardiac catheterization) was associated with a median survival of 12 months. An increased mortality risk was observed among those with iPHT compared with sPHT. This parallels the low survival rate in idiopathic PHT reported in data from the National Heart Lung and Blood Institute Study, which showed a survival of 48% at three years in patients presenting with a mean PASP of 60 mmHg [25]. The survival observed in our patient group is longer than suggested in these published reports. Although mortality is higher than in patients with no organ involvement [22, 23], those with mild and early PHT appear to fare much better than those with established disease.
Our data were collected in an uncontrolled clinical setting and were assembled retrospectively. Observations of this nature are often the only source of clinical material available to guide clinical practice in SSc. However, several issues relating to the study design may have opposing effects on the interpretation of our findings and merit further consideration. First, the observations were carried out in a tertiary referral centre for SSc. Many patients had severe and refractory disease; most had had disease for a number of years before first attending for assessment at the RFH. In this group, the prevalence of severe complications and the mortality rate would have tended to be higher than in community-based samples. Secondly, the follow-up interval varied and the frequency of investigation with Doppler echocardiography increased over time as we became more aware of the high prevalence of PHT and its associated high mortality risk. The result of this practice is that the prevalence of asymptomatic PHT is likely to have been underestimated at the start of the follow-up interval, again making our results overall reflect more severe disease. This is likely to have led us to overestimate the prevalence of the PHT. In addition, the short interval of follow-up in some asymptomatic patients with normal Doppler pressures may have led to their misclassification as being at risk of isolated PHT due to right-censorship of potential cases of secondary disease. Thirdly, all patients in whom PHT was detected received serial courses of i.v. Iloprost. Although the long-term effects of intermittent Iloprost on PHT are not established, it is possible that such therapy may alter the natural history of PHT and reduce mortality. Fourthly, the number of patients in some subgroups was small, and the power of statistical tests relating to risk of progression and mortality was relatively low. The reporting of mortality was also incomplete.
The use of PASP as a process and outcome variable in this analysis also warrants further discussion. PASP may increase for reasons other than precapillary pulmonary hypertension; thus, patients with diastolic left ventricular dysfunction may have elevated pulmonary pressures and apparently normal left ventricular function on echocardiography. This factor may lead to heterogeneity of the study population and may tend to cause overestimation of the actual prevalence of SSc-associated PHT. PASP represents only one aspect of the changes in cardiac function that occur in response to the vasculopathy and pulmonary disease in SSc. Several investigators have shown in studies of idiopathic PHT that mortality is influenced not only by PASP but also by other variables, including right ventricular function, cardiac index and mixed venous oxygen content [26–28]. Changes in the absolute level of PASP, therefore, cannot be interpreted easily in isolation. This is borne out in our data, which show an increased mortality risk even in patients with low and stable pressure. Recent advances in Doppler technology allow much clearer measurement of right ventricular functioning through measurements of right ventricular wall thickening and Doppler-derived velocity changes. These measurements may in the future provide valuable prognostic information in patients with SSc and PHT.
In summary, our findings show a prevalence of PHT among our clinic population of around 10%. The mortality among those in whom mild PHT was detected by Doppler echocardiography was lower than that reported in series of patients with severe and established disease. However, these patients' survival rates were still substantially higher than for SSc without internal organ involvement. Our interpretation is that these findings provide justification for screening all patients with SSc by Doppler echocardiography. Our findings also support the case for serial monitoring to identify subjects with rapidly rising pressures so that this group can be targeted for aggressive treatment. The stable (and on occasions falling) pressures observed in patients with mild PHT are a source of optimism that there may be a therapeutic window in which treatment may be beneficial.
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Notes |
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Correspondence to: A. J. MacGregor, Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
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