Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests

Objective

To construct a readily applicable formula for selecting patients with systemic sclerosis (SSc) for right‐sided heart catheterization (RHC) based on the results of their pulmonary function tests (PFTs).

Methods

The diagnostic value of PFT variables was quantified in 386 patients with SSc against data obtained from RHC.

Results

We derived the following formula using data from 257 patients: predicted mPAP = 136 – SpO ₂ – 0.25 × DLCO % predicted, where mPAP is the mean pulmonary artery pressure, SpO ₂ is the oxygen saturation as measured by pulse oximetry, and DLCO is the diffusing capacity for carbon monoxide. We validated the formula in the remaining 129 SSc patients. The area under the curve was 0.75 (95% confidence interval [95% CI] 0.67, 0.84). Using a predicted threshold of 25 mm Hg, the sensitivity was 90.1% (95% CI 82, 96) and the specificity was 29.2% (95% CI 17, 44). When used as a screening procedure in a typical scleroderma patient population, it is projected that those with an mPAP below 25 mm Hg are unlikely to have pulmonary hypertension (PH; prevalence 4.4%), those with a predicted mPAP of 25–35 mm Hg are at average risk of having PH (prevalence of 11.3%), and those with a formula‐predicted mPAP above 35 mm Hg are likely to have PH (prevalence of 62.9%), thus justifying RHC. In patients with equivocal findings on echocardiography, a high formula‐predicted mPAP is strongly associated with the presence of PH.

Conclusion

We derived and validated an easily applied formula for determining pulmonary function in patients with SSc that identifies subgroups with a low, average, or high prevalence of PH. It provides information that is complementary to echocardiography and that should improve the selection of patients for RHC.

     

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.     

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.     

Treatment of pulmonary arterial hypertension associated to systemic sclerosis

PURPOSE: Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms. CURRENT KNOWLEDGE AND KEY POINTS: Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution. FUTURE PROSPECTS AND PROJECTS: Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.     

Relationship between YKL-40 and pulmonary arterial hypertension in systemic sclerosis

Abstract

Objectives: Systemic sclerosis (SSc) is an intractable connective tissue disease that causes skin and organ fibrosis. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) affect its prognosis. YKL-40 protein impacts inflammation and tissue remodeling. Therefore, we evaluated the utility of YKL-40 blood levels in identifying patients with SSc complicated by PAH, as confirmed by immunohistochemistry (IHC) examination.

Methods: We retrospectively analyzed 78 patients with SSc and performed IHC on 7 normal and 7 SSc skin samples in the Japanese population. Age-adjusted YKL-40 serum levels were analyzed.

Results: YKL-40 age percentile was significantly elevated in SSc patients. There was no difference between patients with SSc with and without ILD and PAH. YKL-40 age percentile was greater in patients with PAH complication. YKL-40 immunostaining was negative in normal skin and prominent in the subcutaneous vascular wall of all SSc samples. Receiver operating characteristic (ROC) curve analysis indicated that YKL-40 age percentile correctly differentiated between patients with and without PAH with a sensitivity of 80% and a specificity of 94.1%.

Conclusion: A higher YKL-40 level with PAH may be reflective of angiogenesis due to capillary injury in SSc. YKL-40 may offer a useful and easily applicable diagnostic biomarker of SSc complicated with PAH.     

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.     

Therapy of pulmonary arterial hypertension in systemic sclerosis: An update

Pulmonary arterial hypertension (PAH) affects 10% to 15% of patients with systemic sclerosis and is a major cause for disease-related morbidity and mortality. Over the past decade, significant progress has been made in the understanding of the pathophysiologic mechanisms underlying PAH. This progress led to the development of several new treatment options and, as a result, dramatically improved survival among this severely affected cohort. The outcome in patients with scleroderma-related PAH is much worse than that in patients with idiopathic PAH, and unfortunately only a few studies have assessed treatment and outcome among patients suffering from connective tissue disease-related PAH. In recent years, publications of connective tissue disease subgroup analysis from large trials in PAH have emerged. We review the current treatment options for PAH and the evidence for their use in scleroderma-related PAH.     

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.     

Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis

Forty-nine patients with progressive systemic sclerosis who had undergone extensive studies including pulmonary artery catheterization as part of an ongoing prospective study of the natural course of progressive systemic sclerosis were evaluated. The overall prevalence of pulmonary arterial hypertension in this population of patients with progressive systemic sclerosis was 33 percent, and among 10 subjects with the CREST syndrome the prevalence of pulmonary hypertension was 50 percent. The relation between pulmonary arterial hypertension documented at catheterization and abnormal results of noninvasive studies suggesting pulmonary hypertension, including physical examination, chest x-ray, electrocardiography, echocardiography, single-breath diffusing capacity, and vital capacity, was studied. Diffusing capacity was significantly lower in those patients with definite pulmonary hypertension (mean pulmonary artery pressure of 22 mg Hg or more) compared with those with a normal mean pulmonary artery pressure, and a diffusing capacity below 43 percent of predicted showed the greatest sensitivity (67 percent) of any single diagnostic test in detecting definite pulmonary hypertension. Chest x-ray suggesting pulmonary hypertension was the least sensitive of the tests evaluated, but showed the greatest specificity (100 percent) in identifying patients with pulmonary hypertension. A classification matrix based on discriminant function analysis utilizing the combination of diffusing capacity below 43 percent of predicted and chest x-ray and electrocardiographic findings correctly identified 75 percent of patients with definite pulmonary hypertension and 97 percent of patients with a normal pulmonary artery pressure, but failed to identify correctly patients with mild pulmonary hypertension (mean pulmonary artery pressure of 20 mm Hg). These findings indicate that specific noninvasive studies are helpful in assessing the likelihood of normal or definitely elevated pulmonary artery pressures in patients with progressive systemic sclerosis, but patients with mild pulmonary hypertension are not likely to be identified by these noninvasive studies.     

Need for improved outcome measures in pulmonary arterial hypertension related to systemic sclerosis

SSc-pulmonary disease is a devastating condition Pulmonary disease is a frequent complication of systemic sclerosis(SSc) and is at the same time challenging for the treating physician.Besides lung fibrosis, pulmonary arterial hypertension (PAH)—definedas a mean pulmonary artery pressure above 25 mmHg at rest orabove 30 mmHg during exercise by right heart catheterization—canoccur both in the limited and diffuse subset of SSc and leadsto right cardiac overload with exercise intolerance, dyspneaand arrhythmia [1]. The natural history of PAH associated withSSc (APAH/SSc) is devastating. While 1-, 3- and 5-yr survivalrates after diagnosis in the idiopathic form (IPAH) are 68,48 and 34% (median life expectancy 2.8 yrs) in untreated patients,several studies have shown that the prognosis in APAH/SSc iseven worse. Median survival in untreated patients is only 12months, and the risk of death is nearly tripled [2     

Screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review.

Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated.     

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.     

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.