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(Chest. 2003;124:2098-2104.)
© 2003 American College of Chest Physicians

Age and Risk of Pulmonary Arterial Hypertension in Scleroderma*

Lionel Schachna, MBBS, FRACP, PhD; Fredrick M. Wigley, MD; Betty Chang, MD, CM, PhD; Barbara White, MD; Robert A. Wise, MD, FCCP and Allan C. Gelber, MD, MPH, PhD

From the Divisions of Rheumatology (Drs. Schachna, Wigley, and Gelber) and Pulmonary and Critical Care Medicine (Drs. Chang and Wise), Johns Hopkins University School of Medicine; and Division of Rheumatology, University of Maryland School of Medicine (Dr. White), Baltimore, MD.

Correspondence to: Lionel Schachna, MBBS, FRACP, PhD, Department of Rheumatology, Austin & Repatriation Medical Centre, Locked Bag 25, Heidelberg, VIC 3084, Australia


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To investigate whether age at disease onset is a risk factor for pulmonary arterial hypertension (PAH) in scleroderma.

Setting: Scleroderma center.

Patients: Seven hundred nine consecutive scleroderma patients who underwent echocardiography.

Measurements: The risk of PAH associated with age at disease onset was modeled as both a continuous and categorical variable. Risk estimates were adjusted for sex, race, scleroderma subtype, disease duration, smoking status, FVC, anticentromere and antitopoisomerase I antibody status.

Results: Overall, 274 patients (38.6%), 272 patients by Doppler echocardiography and 2 patients by M-mode echocardiography, had PAH at baseline or during follow-up. There were 114 patients with mild PAH (right ventricular systolic pressure [RVSP], 36 to 45 mm Hg), 66 patients with moderate PAH (RVSP, 46 to 55 mm Hg), and 92 patients with severe PAH (RVSP >= 56 mm Hg). A 52% increase in risk of PAH was demonstrated for every 10 years of age at disease onset (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.31 to 1.76). In addition, there was a twofold greater risk of PAH (OR, 2.30; 95% CI, 1.32 to 3.99) for late-onset (age >= 60 years) vs earlier-onset (< 60 years) disease. These associations remained evident and were somewhat strengthened when the analyses were restricted to patients with moderate and severe PAH.

Conclusions: We identified increasing age at scleroderma onset as a risk factor for PAH. Vigilance among these high-risk patients may provide an opportunity to intervene prior to development of irreversible pulmonary vascular disease.

Key Words: age • echocardiography • late onset • pulmonary arterial hypertension • scleroderma


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In scleroderma, pulmonary arterial hypertension (PAH) represents a leading cause of mortality,1 2 3 yet there are few recognized predictors for this disease manifestation. The limited form of scleroderma is associated with an increase in risk of isolated PAH that occurs late in the disease course.4 5 Several serologic abnormalities also confer increased susceptibility to PAH, including antiendothelial cell,6 7 anticardiolipin,8 and antifibrillarin antibodies.9 10 We hypothesized that advancing age may represent such a predictor, but its relationship to PAH in scleroderma has not been clearly defined.

Evidence from observational studies has demonstrated that aging modifies the clinical and serologic phenotype of several other autoimmune rheumatic disorders, including systemic lupus erythematosus,11 12 13 rheumatoid arthritis,14 15 16 17 inflammatory myositis,18 19 and Sjögren syndrome.20 Yet, few studies have examined the relationship of age to clinical phenotype in scleroderma, nor to the risk of PAH in particular. Initial case reports in the 1970s characterized late-onset scleroderma as typically of the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia) variant with few organ complications.21 22 This characterization was subsequently challenged by case series of late-onset scleroderma typified by a rapidly fatal course.23 24 A recent survey that specifically addressed the influence of age among 150 patients with scleroderma found that those > 50 years old at disease onset were more likely to have limited cutaneous involvement, secondary Sjögren syndrome, and anticentromere antibodies (ACAs); PAH was, however, not evaluated as an outcome in this study.25 Several other reports5 26 27 28 examined age in relation to PAH but found no differences; these studies were not sufficiently powered to detect differences in age and did not perform multivariate analysis to adjust for potential confounding. Of note, the findings of a recent longitudinal study29 suggested that postmenopausal women were at increased risk of PAH. To date, a study specifically examining the relationship between age across the life spectrum and risk of PAH in scleroderma has not been reported. With these issues in mind, we conducted a large epidemiologic survey to determine whether there was an independent association between age at disease onset and risk of PAH in scleroderma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Sample and Measurements
A total of 899 patients with scleroderma attended The Johns Hopkins and University of Maryland Scleroderma Center over a 4.5-year period between January 1997 and June 2001 (Fig 1 ). Within this cohort, 849 patients (94.4%) satisfied the American College of Rheumatology (ACR) criteria for scleroderma,30 or had at least three features of the CREST syndrome; 50 patients (5.6%) had systemic sclerosis sine scleroderma. The diagnosis of scleroderma was established by two of the authors (Dr. Wigley or Dr. White), two recognized experts in scleroderma. We identified 709 patients (78.9%) who underwent at least one echocardiogram at initial evaluation or during follow-up. Most echocardiograms were performed at Johns Hopkins Bayview Medical Center, where the protocol is to estimate the right atrium-right ventricle gradient using the modified Bernoulli formula P = 4V2 (where P is pressure gradient and V is peak retrograde velocity). The right atrial pressure was nominally estimated at 10 mm Hg, but there was some variability in this practice depending on the interpreting cardiologist, size of inferior vena cava, and respiratory variation in inferior vena cava diameter. Studies from outside laboratories were performed in accordance with their standards of practice. In most cases, we believe that this involved the use of the modified Bernoulli formula but we cannot be certain.



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  		Figure 1.. Study design and determination of PAH.

 
PAH was considered present if the Doppler echocardiography-estimated right ventricular systolic pressure (RVSP) exceeded 35 mm Hg in at least one echocardiogram. The grade of PAH was then categorized as mild (36 to 45 mm Hg), moderate (46 to 55 mm Hg), or severe (>= 56 mm Hg). A total of 507 patients (71.5%) underwent Doppler echocardiography. A further 202 patients (28.5%) underwent M-mode but not Doppler echocardiography. For these patients, PAH was defined by M-mode evidence of right ventricular dilatation together with a structurally normal left ventricle.31 Our study population therefore comprised 709 patients for whom the presence or absence of PAH was determined by Doppler (n = 507) or M-mode echocardiography (n = 202). Of these patients, 285 patients (40.2%) underwent one, 190 patients (26.8%) underwent two, and 234 patients (33.0%) underwent three or more echocardiograms. For those patients who underwent more than one echocardiogram, the decision was made a priori to use the highest grade of PAH in the analyses.

The onset of scleroderma was defined as development of the first clinical feature of scleroderma (usually Raynaud phenomenon).32 We also evaluated the association between age at disease onset and PAH using two alternative definitions of onset: (1) development of the first non-Raynaud phenomenon scleroderma feature, and (2) date of initial physician diagnosis of scleroderma. For patients with PAH, duration of disease was determined from disease onset to the date of first echocardiogram with evidence of PAH. For those without PAH, disease duration was calculated from disease onset to the date of the last performed echocardiogram.

Clinical features recorded at initial presentation to the Scleroderma Center included age, sex, race, smoking status, presence or absence of ACR classification criteria for scleroderma, and disease subtype (limited, diffuse, or sine scleroderma).33 The results of serologic testing were available for 669 patients (94.4%). These included determination of antinuclear antibody titer and pattern, using indirect immunofluorescence with HEp-2 cells as substrate,34 and antitopoisomerase I antibody by standard immunodiffusion techniques.35 ACA was identified by characteristic staining pattern on immunofluorescence. FVC, a measure of lung volume, was available for 644 patients (90.8%). An FVC result < 70% predicted was used as a surrogate for pulmonary fibrosis.

Statistical Analysis
Demographic, clinical, and serologic variables were summarized as means ± SD and proportions. Differences between these summary statistics were analyzed using the Student t test for continuous variables and the {chi}2 test for categorical variables. In our analyses, age was modeled as both a continuous and categorical variable. Logistic regression was performed to estimate the risk of PAH associated with age. Odds ratios (ORs) of PAH are presented for each 10-year period of age at scleroderma onset, and for late-onset (>= 60 years) vs younger-onset (< 60 years) disease. Multivariate analysis was conducted to adjust for sex, race, scleroderma subtype, disease duration, smoking status, FVC, and ACA and antitopoisomerase I antibody status. Additional analyses were performed in which the outcome was restricted to the more severe phenotype of moderate and severe PAH, for which there was intuitively a lower likelihood of misclassification than for the mild grade of PAH. These analyses were also repeated after the cohort was stratified by the following: (1) disease subset (limited vs diffuse disease), and (2) spirometry status (< 70% vs >= 70% predicted FVC). Finally, to account for the expected increase in pulmonary artery systolic pressure (PASP) with aging, we repeated the analyses after redefining PAH as those patients exceeding the upper bound of age- and sex-appropriate normative values.36 In these analyses, we excluded 45 patients with PAH whose PASP no longer exceeded the expected value for age. Statistical analyses were performed using Stata Statistical Software (Release 7.0; Stata Corporation; College Station, TX); reported p values are two sided with {alpha} = 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Table 1 summarizes the demographic, clinical, and serologic features of the study population: 592 women (83.5%), 130 African Americans (18.3%), and 354 former or current smokers (49.9%). In terms of scleroderma subtype, 405 patient had limited (57.1%), 271 patients had diffuse (38.2%), and 33 patients had systemic sclerosis sine scleroderma (4.7%). ACA was identified in 130 patients (19.0%), whereas 89 patients had antitopoisomerase I antibody (13.0%). Mean age at disease onset was 41.8 ± 14.6 years.


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  		Table 1.. Demographic, Clinical, and Serologic Features Among 899 Scleroderma Patients*

 
Overall, 274 patients (38.6%) had PAH at baseline or during follow-up: 272 patients by Doppler echocardiography and 2 patients by M-mode echocardiography (Fig 1) . There were 114 patients with mild, 66 patients with moderate, and 92 patients with echocardiographic evidence of severe PAH. More patients with PAH were of African-American race compared to those without PAH (Table 1) . Additionally, more African Americans than whites had an abnormally low FVC (80 of 118 patients [67.8%] vs 150 of 503 patients [29.8%]; p < 0.001). Not unexpectedly, the frequency of abnormal FVC was greater among patients with PAH compared to those without. Patients with PAH were on average 4.1 years older at disease onset than those without PAH (95% CI, 2.0 to 6.3 years). In addition, duration of disease at the time of echocardiography for those with PAH was 2.0 years longer than for those without PAH (95% CI, 0.4 to 3.6 years). Of note, the characteristics of patients who did not undergo echocardiography closely resembled those without PAH in terms of demographic data, scleroderma features, FVC, and age at disease onset (data not shown).

Table 2 presents the frequency of PAH by decade of age at onset of scleroderma. Across the life spectrum, the risk of PAH tended to increase with each older decade of life at scleroderma onset. The highest risk of PAH was seen among patients with disease onset in the seventh decade (age, 60 to 69 years), in whom 34 of 60 patients (56.7%) acquired disease. In analyses modeling age as a continuous variable, there was a 22% increase in risk of PAH for every 10 years of age at disease onset (OR, 1.22; 95% CI, 1.10 to 1.36) [Table 3 ]. Though the frequency of African-American race was higher among patients with PAH, adjustment for race did not alter the relation of age to PAH. Similarly, the risk of PAH associated with age was neither confounded by longer duration of disease nor by FVC status. The risk associated with increasing age persisted and was strengthened after further adjustment for sex, smoking status, presence or absence of ACR criteria, disease subtype, FVC, and centromere and antitopoisomerase antibody status (OR, 1.52; 95% CI, 1.31 to 1.76). Furthermore, the relation between increasing age and PAH persisted and was somewhat strengthened when the outcome was restricted to moderate and severe PAH.


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  		Table 2.. Frequency of PAH by Decade of Age at Onset of Scleroderma

 

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  		Table 3.. Risk of PAH Associated With Age at Disease Onset in Scleroderma

 
In order to examine the influence of late-onset scleroderma on risk of PAH, we next modeled age as a dichotomous variable: >= 60 years (n = 82) vs < 60 years (n = 627) at disease onset (Table 3) . This age cut-off was selected in order to identify a subgroup of patients with disease onset considerably later than the typical age range of 30 to 50 years.37 Moreover, this analysis represented an alternate approach to testing the hypothesis that older age represents an important risk factor for PAH in scleroderma. The risk of PAH was more than twofold greater for late-onset compared with younger-onset disease in the full multivariate model (OR, 2.30; 95% CI, 1.32 to 3.99). The association between late-onset scleroderma and PAH again remained evident when the outcome was restricted to moderate and severe PAH. Because fewer patients were included in this final analysis, the CIs surrounding these risk estimates were wider. Importantly, the internal validity of these analyses was not compromised by a greater number of echocardiography examinations among subjects with late-onset compared to younger-onset scleroderma (2.4 ± 1.7 vs 2.4 ± 1.8, p = 1.0).

In analyses stratified by disease subtype, increasing age remained associated with an increase in risk of PAH in both the limited and diffuse subtypes, after adjusting for potential confounding variables (limited: OR, 1.48; 95% CI, 1.21 to 1.80; diffuse: OR, 1.63; 95% CI, 1.28 to 2.08). Similarly, in analyses stratified by spirometry status, increasing age remained a risk factor for PAH in the strata with normal (OR, 1.53; 95% CI, 1.24 to 1.89) and reduced FVC (OR, 1.53; 95% CI, 1.22 to 1.93).

Results were unchanged when the analyses were repeated using the two alternative definitions for disease onset, namely age at onset of first non-Raynaud phenomenon scleroderma feature, and age at physician diagnosis of scleroderma (data not shown). The results were also unchanged when the analyses were limited to those who underwent Doppler echocardiography (data not shown). Finally, when PAH was redefined as those exceeding age- and sex-appropriate normative values,36 the adjusted OR of PAH was 1.45 (95% CI, 1.22 to 1.73) when age was modeled as a continuous variable, and 1.96 (95% CI, 1.00 to 3.84) when age was modeled as a dichotomous variable.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this large scleroderma cohort, we identified increasing age at disease onset as a risk factor for PAH. There was an approximately 50% increase in risk of PAH for every 10 years of age at onset of scleroderma after adjustment for demographic and clinical parameters. The oldest patients (>= 60 years) had substantially higher risk of PAH, twice as high as those with earlier-onset disease. Furthermore, the association between increasing age and PAH remained evident when the outcome was restricted to moderate and severe PAH, those grades of PAH that are often associated with major morbidity and mortality. Moreover, despite the expected increase in PASP with aging, older age remained significantly associated with PAH in analyses using age- and sex-appropriate normative definitions of PAH.

The influence of age at disease onset on clinical phenotype has previously been characterized in several systemic rheumatic disorders other than scleroderma. For example, late-onset rheumatoid arthritis is associated with early inflammatory activity,17 while late-onset systemic lupus erythematosus is characterized by a lower incidence of renal and neuropsychiatric complications.38 39 In addition, patients who are older at the onset of inflammatory myositis have increased esophageal involvement,19 while aging influences serologic abnormalities rather than clinical manifestations of Sjögren syndrome.20

With regard to scleroderma, however, only a handful of reports have specifically evaluated the influence of late-onset disease on clinical phenotype.21 22 23 24 25 Interestingly, in an American study27 that addressed the prevalence of PAH in scleroderma, mean age at disease onset was approximately 5 years older for those patients with PAH compared to those without PAH. In contrast to our findings, this age difference was not statistically significant. This study, which included only 12 patients with PAH, as well as several other studies,5 26 28 were not sufficiently powered to detect these differences. In a prospective study3 from the United Kingdom, late-onset scleroderma was associated with a 74% increase in risk of rapid progression of PAH, although the CIs surrounding this estimate were wide and contained unity.

Why late-onset scleroderma should be associated with an increase in risk of PAH is uncertain. Like systemic vascular resistance, pulmonary vascular resistance increases with age,40 probably due to reduced compliance of the pulmonary vascular bed.41 42 43 In scleroderma, aging may promote the development of PAH via several important pathogenic pathways. First, aging tends to reduce endothelial release of nitric oxide and endothelium-dependent relaxation by acetylcholine.44 45 Second, spontaneous endothelial injury, possibly as a result of the generation of excess oxygen-derived free radicals and defective in vivo endothelial repair mechanisms, increases in older individuals.46 47 48 49 Third, changes in immune reactivity with aging (termed immunescence) include aberrant T-cell proliferation and increased production of autoantibodies.50 These aging-related changes in vascular biology may render the pulmonary arterial tree particularly susceptible to the pathophysiologic mechanisms observed in scleroderma.

The strengths of our study include the large cohort size, collection of extensive data on potential confounders, and a relatively large proportion of the cohort who underwent echocardiography. The validity of our findings is further supported by a consistent relationship using three alternative definitions of scleroderma onset: onset of first clinical feature of scleroderma, onset of first non-Raynaud phenomenon scleroderma feature, and age at physician diagnosis. Nevertheless, several limitations of our study need to be addressed. First, the patients were recruited from a scleroderma referral center and may therefore manifest a more severe phenotypic expression. Second, we used echocardiography to establish the presence of PAH rather than right-heart catheterization. This noninvasive tool, however, is now routinely used in clinical practice to provide an estimate of RVSP in a variety of cardiopulmonary disorders.51 Parallel echocardiography/right-heart catheterization studies31 52 have established the validity and reliability of Doppler echocardiography for estimating RVSP in scleroderma patients. Moreover, we deliberately used the least equivocal and most specific M-mode criteria for PAH in order to avoid overdiagnosis of PAH in those with M-mode studies.31 Third, echocardiography was not uniformly obtained in all patients attending the Scleroderma Center, introducing the risk of selection bias. Importantly, the characteristics of patients who did not undergo echocardiography closely resembled those without PAH, suggesting that this group represented patients who were less likely to acquire PAH. Fourth, there is potential for misclassification for patients with borderline elevation of RVSP.31 For this reason, we specifically reanalyzed the relationship of age to PAH after restricting the outcome to the moderate and severe grades of PAH. In these analyses, the findings were confirmed and even somewhat strengthened. Fifth, we did not measure antiendothelial cell, anticardiolipin, and antifibrillarin antibodies and were therefore unable to adjust for these potential confounding serologic measures.

Finally, in the absence of routine chest imaging, we were unable to determine with direct evidence whether the patients in our study population manifested radiographic features of pulmonary parenchymal disease. To address this limitation, we utilized FVC, a well-accepted spirometric measure of restrictive lung disease, as a surrogate for underlying parenchymal disease. A normal FVC is likely to indicate the absence of clinically significant pulmonary fibrosis. The analysis in which the cohort was stratified by reduced vs normal FVC status provided indirect evidence that age was a risk factor of PAH, in the presence and in the absence of underlying pulmonary parenchymal disease. Despite these limitations, this study represents a systematic investigation using echocardiography, a routinely employed and validated diagnostic tool in clinical practice, in the detection of PAH.

In conclusion, increasing age at disease onset represents a risk factor for PAH in our scleroderma cohort. The major clinical implication of this finding is that physicians should monitor those patients who acquire scleroderma later in life for PAH. As therapeutic strategies are rapidly evolving,53 identification of PAH among high-risk scleroderma patients may provide an opportunity to intervene prior to development of irreversible pulmonary vascular disease.


   Acknowledgements
 
We thank Christy Boling, Arash Banuwal, and Maria Fiesta for managing The Johns Hopkins and University of Maryland Scleroderma Center Database; and Gwen Leatherman, RN, and Jane Hofherr, RN, for their dedication to our Scleroderma Center and patients.


   Footnotes
 
Abbreviations: ACA = anticentromere antibody; ACR = American College of Rheumatology; CI = confidence interval; PAH = pulmonary arterial hypertension; OR = odds ratio; PASP = pulmonary artery systolic pressure; RVSP = right ventricular systolic pressure

This study was supported by a Maryland Chapter Arthritis Foundation Institutional Grant, the Scleroderma Research Foundation, and the Jack Alfano, Joachim & Nancy Bechtle and Don & Nancy Powell Research Funds.

Dr. Schachna was supported by an Arthritis Foundation Postdoctoral Fellowship Award.

Dr. Gelber was supported by an Arthritis Foundation Arthritis Investigator Award and Maryland Chapter Grant.

Received for publication December 27, 2002. Accepted for publication July 17, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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