Reduced exercise capacity in systemic sclerosis patients without pulmonary involvement

OBJECTIVE: To evaluate the exercise capacity of women with systemic sclerosis (SSc) without pulmonary involvement using a cardiopulmonary stress test. METHODS: Thirteen consecutive female SSc patients [mean age 40.8+/-14 years, mean body mass index (BMI) 25.5+/-3.7 kg/m2] without pulmonary and cardiac involvement and 13 healthy sedentary female controls (mean age 41.6+/-9.1 years, mean BMI 23.7+/-3.8 kg/m2) matched by age and BMI underwent a maximum cardiopulmonary stress test (Bruce protocol). The following parameters were analysed: peak oxygen uptake (VO2peak), anaerobic threshold (AT), respiratory compensation point (RCP) and metabolic equivalent (MET) of the VO2peak. Comparisons between groups were analysed using the Student t-test. RESULTS: Forced vital capacity (FVC; 92.2+/-14.2% predicted) and carbon monoxide diffusion lung capacity (DL CO; 85.8+/-5.8% predicted) were within the normal range in SSc patients. VO2peak of SSc patients was significantly reduced in comparison to the control group (19.8+/-4.6 vs. 23.7+/-4.5 mL/kg/min, p = 0.04). SSc patients also had a significant reduction in MET at peak exercise (5.6+/-1.3 vs. 6.7+/-1.3 MET, p = 0.04) and a significant shorter time interval between AT and RCP compared to the control group (112.6+/-95.6 vs. 164.0+/-65.3 s, p = 0.03). CONCLUSION: SSc patients without pulmonary impairment have reduced exercise capacity. Abnormal vascular response to exercise may account for this finding, as the vascular system is one of the major target organs in this pathological condition.     

Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis

INTRODUCTION: Pulmonary arterial hypertension (PAH) is the most common cause of scleroderma-related deaths. New medications for PAH patients make it necessary to identify patients with high risk factors for PAH. This study looks at the use of an exercise echocardiogram in identifying patients who may have PAH and may be candidates for early therapeutic intervention. METHODS: This study included 54 scleroderma patients with symptoms suggesting they were at risk for pulmonary hypertension, including dyspnea on exertion, diffusing capacity of the lung for carbon monoxide (Dlco)<60% of predicted, FVC<70% of predicted, percentage of predicted FVC/percentage of predicted Dlco (FVC%/Dlco%) ratio>1.6, or resting right ventricular systolic pressure (RVSP)>35 mm Hg. The exercise echocardiogram protocol involved the standard Bruce stress echocardiogram protocol with remeasurement of the RVSP within 1 min of stopping exercise. A positive exercise test result was defined as an increase of at least 20 mm Hg in the RVSP with exercise. Right-heart catheterization with exercise was performed in those with a positive exercise test result. RESULTS: Resting mean RVSP was 34.5 mm Hg, which increased to 51.4 mm Hg with exercise; 44% had at a positive exercise test result, which correlated with a low Dlco, high FVC%/Dlco% ratio (p<0.001), a positive anti-centromere antibody, and RVSP>35 mm Hg (p<0.05). PAH was confirmed by right-heart catheterization in 81% of patients: 19% at rest and 62% of patients with exercise. CONCLUSIONS: Exercise-induced pulmonary hypertension is a common finding in patients at high risk for PAH. This may be a sensitive way to identify patients with early PAH. Long-term follow-up and early treatment should be studied in these patients.     

Interstitial lung disease in systemic sclerosis

Lung involvement frequently complicates systemic sclerosis (SSc), provoking loss of quality of life and a poor expectation of survival. For this reason an early diagnosis of lung involvement is warranted: high-resolution computed tomography (HRCT), pulmonary function tests (PFT), lung scintigraphy with DTPA and bronchoalveolar lavage (BAL) are mandatory to define and follow-up pulmonary interstitium. Coughing and a sensation of breathlessness on exertion are the earliest symptoms of lung involvement. Lung involvement may be investigated with PFTs, which are non-invasive and require breathing into a tube via a mouthpiece. Forced vital capacity, which measures the total amount of air capable of being blown forcefully, and the diffusion capacity for carbon monoxide, a measure of how well oxygen diffuses into blood, are the most important functional measures. A routine chest X-ray may demonstrate fibrosis, but it is not very sensitive for detecting early or mild disease. For this reason, a HRCT scan is required. This non-invasive investigation provides images of multiple slices through the lung, from top (apex) to bottom (base), and can even detect lung involvement in early phases when no symptoms are present. ^99mT-DTPA is recommended in those patients with isolated diffusion deficits on lung function tests and in addition to HRCT in confirming the suspicion of vascular disease rather than early fibrosing alveolitis. Bronchoscopy with BAL is an invasive test that also may provide information about the inflammatory status of the affected areas of the lung detected during HRCT. In order to detect alveolitis, it should be performed as early as possible, to start prompt immunosuppressive treatment.     

Interstitial lung disease in systemic sclerosis

Systemic sclerosis is a multisystem disorder of unknown etiology and involves organ systems such as the skin, peripheral vasculature, gastrointestinal tract, kidney, heart, and the lungs is observed quite frequently. In this review, we discuss the development of interstitial lung disease, one of the common pulmonary manifestations and a major cause of mortality and morbidity in this disorder. It is, however, under-recognized and diagnosed late in the course of the illness. Early use of pulmonary function tests followed by bronchoalveolar lavage in appropriate cases helps in early diagnosis. Recent studies emphasize the role of various profibrotic and inflammatory cytokines both locally in the lung and systemically in its pathogenesis. Treatment is helpful in arresting the progression if initiated early. Cyclophosphamide with or without corticosteroids given orally or as intravenous pulse may be helpful.     

Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis

Pulmonary arterial hypertension (PAH) is the major complication of systemic sclerosis (SSc) and the main cause of morbi-mortality. It is important to find predictors for this vascular problem. The objective of this study was to determine the serum levels of different biomarkers in patients with SSc and secondary PAH and to compare them with those of healthy control subjects to define their potential role as predictors of PAH. Cross-section study in which 20 patients with SSc were included. PAH was diagnosed by echocardiogram. The optical densities of endoglin (Eng), endothelin-1 (ET-1), platelet-derived growth factor (PDGF), tumoral necrosis factor alpha (TNF-α), Transforming growth factor beta 2 (TGF-β2) and Interleukin 8 (IL-8) were measured in 20 patients with SSc and 20 healthy controls matched by sex. The differences found between the group of patients with PAH and the control group were (mean or median and range): ET-1 (0.20; 0.10–0.35 vs. 0.16; 0.10–0.24; P = 0.0276), IL-8 (195.7; 45.5–504 vs. 118.9; 23–299.5; P = 0.0364), TNF-α (0.70; 0.50–0.96 vs. 0.48; 0.38–0.65; P = 1 × 10⁻⁸) and Eng (0.95; 0.57–1.72 vs. 0.75; 0.57–0.89; P = 0.0028). A correlation was found between the progression of the disease and the development of Raynaud’s phenomenon (Rho: 0.67 and P = 0.0011), ET-1 and Eng (Rho: 0.53 and P = 0.0196), and between IL-8 and Eng (Rho: 0.68 and P = 0.0019). In conclusions, the elevation of the serum levels of Eng and ET-1 could represent a useful tool as PAH biomarkers. Nevertheless, the diagnostic value of these markers needs to be determined by prospective studies. Drs. P. Coral-Alvarado and G. Quintana contributed equally to this work and both should be considered as first authors.     

Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis

STUDY OBJECTIVES: The goal of this study was to determine whether the survival of patients with pulmonary hypertension related to systemic sclerosis (SScPH) was different from that of patients with other forms of pulmonary arterial hypertension. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS: Our cohort was composed of 33 patients with pulmonary hypertension that is sporadic, familial, or related to anorexigen use (PPH) and 22 patients with SScPH who underwent initial pulmonary artery catheterization and vasodilator study at our center between January 1997 and June 2001. Measurements and results: Patients with SScPH had somewhat lower percentage of predicted lung volumes than patients with PPH (total lung capacity, 80% vs 92%; p = 0.06) and had lower percentage of predicted diffusion capacity of the lung for carbon monoxide (42% vs 68%; p = 0.0002). Right atrial pressure, pulmonary artery pressure, and cardiac index were similar between the groups. Patients with SScPH and PPH were treated with usual medical therapies, such as digoxin, warfarin, and continuous IV epoprostenol. Despite these similarities, the risk of death in patients with SScPH was higher than in patients with PPH (unadjusted hazard ratio, 2.9; 95% confidence interval, 1.1 to 7.8; p = 0.03). This increased risk appeared to persist after adjustment for a variety of demographic, hemodynamic, or treatment variables. CONCLUSIONS: Despite having similar hemodynamics, patients with SScPH have a higher risk of death than patients with PPH. Future studies of the mechanism and therapy of pulmonary arterial hypertension should focus on the distinctions between the different forms of this disease.     

Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

High incidence of pulmonary arterial hypertension in systemic sclerosis patients with anti-centriole autoantibodies

Abstract

Systemic sclerosis (SSc)-related autoantibodies are useful tools in identifying clinically homogenous subsets of patients and predicting their prognosis. In this report, we described five SSc patients with anti-centriole antibodies. All five patients were females and had digital ulcers/gangrene. Four of five (80%) patients had pulmonary arterial hypertension (PAH). None of the five patients had active pulmonary fibrosis or developed renal crisis. Anti-centriole antibodies may be a marker for PAH and digital ulcers/gangrene.     

Bosentan ameliorated exercise-induced pulmonary arterial hypertension complicated with systemic sclerosis

Pulmonary arterial hypertension (PAH) is a frequent complication in patients with systemic sclerosis. Bosentan is used in patients with symptomatic PAH; however, it has not been established whether or not bosentan ameliorates the progression of PAH in patients with no PAH-related symptoms. We present a case of systemic sclerosis with no PAH-related symptoms in which bosentan ameliorated exercise-induced PAH evaluated by 6-minute walk stress echocardiography, brachial flow-mediated dilation, and skin temperature of hands and feet. The results suggest that administration of bosentan in patients with early-stage PAH ameliorates pulmonary arterial vasodilatation through improvement of endothelial function.     

Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis

Background

Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc.

Methods and results

We prospectively enrolled 63 patients with SSc (age 54 ± 3 years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mm Hg and EIPH as sPAP > 50 mm Hg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP) = 1.9 + 1.24 × left ventricular (LV) E/e′ and pulmonary vascular resistance (PVR) = (mPAP–LAP) / LV cardiac output (CO) and slope of mPAP–LVCO relationship = changes in mPAP / changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mm Hg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p = 0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mm Hg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP–LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mm Hg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β = 3.1 ± 0.8; p = 0.001) and exercise PVR (β = 7.9 ± 1.7; p = 0.0001) were independent determinants of exercise sPAP.

Conclusion

EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR.     

Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease

OBJECTIVE: To determine whether pulmonary arterial hypertension (PAH) is a prognostic factor for mortality in diffuse cutaneous systemic sclerosis (dcSSc), independent of interstitial lung disease (ILD). METHODS: ILD was diagnosed by high-resolution computed tomography and PAH (pulmonary arterial systolic pressure [PASP] > or =45 mm Hg) by echocardiography. All patients with ILD underwent testing for total lung capacity (TLC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide. RESULTS: Eighty-six patients with dcSSc (mean age at diagnosis 44.5 years) were followed up for a median of 72.5 months. ILD was found in 52 patients (60%) and PAH in 18 (21%). ILD was associated with PAH in 15 patients. Seventeen patients died (19.8%), 9 of whom had PAH (P = 0.001) and 10 of whom had ILD (P = 0.99). By multivariate analysis, age at SSc diagnosis and PAH were the only independent predictors of death (hazard ratio [HR] 1.057, 95% confidence interval [95% CI] 1.009-1.109, P = 0.020 and HR 4.09, 95% CI 1.47-11.5, P = 0.007, respectively). Mean TLC and mean FVC were similar in ILD patients with and those without PAH (P = 0.71 and P = 0.40, respectively). Among ILD patients, age at SSc diagnosis and PAH were again the sole predictors of death (HR 1.073, 95% CI 1.003-1.149, P = 0.042 and HR 5.07, 95% CI 1.09-23.8, P = 0.038, respectively). Twenty ILD patients received at least 6 monthly pulses of intravenous cyclophosphamide (CYC). In CYC-treated patients with PAH (n = 8), PASP increased significantly during the CYC regimen (mean +/- SD 55 +/- 14.5 mm Hg; P = 0.015 versus baseline), while TLC remained stable during the same period. CONCLUSION: These results indicate that, independent of ILD, PAH is a major prognostic factor for survival in dcSSc.