Pulmonary Hypertension In Scleroderma Research Articles

Pulmonary Hypertension in Scleroderma– Evaluation and Management

Pulmonary Arterial Hypertension (PAH) is a clinical syndrome consisting of physiologic/hemodynamic criteria that are a consequence of several etiologies. Systemic Sclerosis (SSc), one of the most common causes of PAH, is an autoimmune disorder of the connective tissue leading to fibrosis that involves the skin, gastrointestinal tract, lungs, heart, kidney etc. SSc has an annual prevalence of one to five cases for every 1000 individuals and nearly 15 percent of all cases develop PAH.At its core, Pulmonary hypertension (PH) in SSc is an obliterative vasculopathy in small to medium-sized pulmonary arterioles. A host of other local and systemic mechanisms operate in concert to gradually alter the hemodynamics resulting in elevated pulmonary vascular resistance and thus right ventricular afterload. A diagnosis of PAH in SSc is virtually a death sentence, with studies reporting a mortality rate of 50 per cent in the 3 years of diagnosis. Therefore, developing and implementing a robust screening and diagnosis protocol is crucial in the fight against this pervasive disease.This review aims to summarize the current literature of PAH in SSc, with a special focus on the screening and diagnosis protocols, newer treatment options and prognostic indicators for the same.

Impact of concomitant obstructive sleep apnea on pulmonary involvement and main pulmonary artery diameter in adults with scleroderma

PurposePulmonary involvement is common in adults with scleroderma. The effect of concomitant obstructive sleep apnea (OSA) on risk for pulmonary hypertension in scleroderma is unknown. An enlarged main pulmonary artery diameter (mPAD) derived from chest computer tomography (CT) is a useful predictor of pulmonary hypertension. We addressed the effect of OSA on pulmonary involvement and enlarged mPAD in adults with scleroderma.MethodsAll participants underwent pulmonary function testing, carbon monoxide diffusion capacity, chest CT, and overnight sleep recording with home sleep apnea testing. OSA diagnosis was based on an apnea-hypopnea index (AHI) ≥ 15/h. Oxygen desaturation index (ODI) was also recorded. Scleroderma involvement of the lungs was defined as the Warrick score ≥ 7 based on the CT findings. Enlarged mPAD was defined as an mPAD ≥ 29 mm in men and ≥ 27 mm in women.ResultsAfter exclusions, 62 patients (58 women) were included. OSA was found among 20 (32%), 17/42 (38%) in the limited cutaneous type, and 3/20 (15%) in the diffuse cutaneous type (p = 0.08). Scleroderma involvement of the lungs was observed in 40 participants (65% in OSA vs 64% in no-OSA; n.s.). Enlarged mPAD was measured in 16 participants, 10 of 20 (50%) in the OSA group and 6 of 17 (14%) in the no-OSA group (p = 0.003). OSA was associated with enlarged mPAD (odds ratio 4.7, 95% confidence interval 1.1–20.9; p = 0.042) independent of age, body mass index, and pulmonary involvement. There was a linear relationship between mPAD and AHI (r = 0.37; p = 0.003) as well as ODI (r = 0.41; p < 0.001).ConclusionsIn this cohort, OSA was associated with risk for pulmonary hypertension independent of pulmonary involvement. These findings suggest that assessing the effect of therapy for concomitant OSA in patients with scleroderma is warranted.Trial registrationNCT 02740569

Clinical ultrasonography in systemic autoimmune diseases

Clinical ultrasonography should be considered a complementary examination that can change clinical practice, as well as a tool to add to the medical history.Systemic autoimmune diseases (SAD) can involve numerous structures and organs. Ultrasonography has broad applied utility in detecting complications such as the presence of free intraabdominal, pleural and pericardial fluid in polyserositis, left ventricular systolic dysfunction in myocarditis and deep vein thrombosis in antiphospholipid syndrome.Specifically for SAD, ultrasonography helps examine the salivary glands in Sjögren's syndrome, determines the presence of the halo sign in giant cell arteritis and the presence of tendon or joint inflammation, quantifies pulmonary hypertension in scleroderma and assesses the presence of interstitial pulmonary disease in dermatomyositis.Clinical ultrasonography performed by internists is therefore an extremely useful technique in the diagnosis and follow-up of patients with SAD.

Ecografía clínica en las enfermedades autoinmunes sistémicas

Clinical ultrasonography should be considered a complementary examination that can change clinical practice, as well as a tool to add to the medical history.Systemic autoimmune diseases (SAD) can involve numerous structures and organs. Ultrasonography has broad applied utility in detecting complications such as the presence of free intraabdominal, pleural and pericardial fluid in polyserositis, left ventricular systolic dysfunction in myocarditis and deep vein thrombosis in antiphospholipid syndrome.Specifically for SAD, ultrasonography helps examine the salivary glands in Sjögren's syndrome, determines the presence of the halo sign in giant cell arteritis and the presence of tendon or joint inflammation, quantifies pulmonary hypertension in scleroderma and assesses the presence of interstitial pulmonary disease in dermatomyositis.Clinical ultrasonography performed by internists is therefore an extremely useful technique in the diagnosis and follow-up of patients with SAD.

Does Etiology of Pulmonary Hypertension Impact Survival? An ISHLT Registry Analysis

Purpose Various etiologies of pulmonary hypertension (PH) and their comorbidities may impact post-lung transplantation (LTx) outcomes. We hypothesized that primary PH, scleroderma PH, and other secondary PH differ in post-tx survival. Methods ISHLT registry was investigated (05/06/2005 -12/31/2016) for bilateral LTx patients > 18 yo excluding multi-organ tx, redo tx, or lobar tx. Primary diagnosis for tx divided as follows: Primary PH (PPH), other Secondary PH (SPH), scleroderma PH (sclPH), and non PH. Age and gender PPH against all 3 groups p Results Kaplan Meier survival (days, mean) PPH (n=937) 2677 (CI 2530, 2824); SPH (n=173) 1953 (CI 1695, 2212); non PH (n=27449) 2664.0 (CI 2633, 2694); SclPH (n=221) 2448.4 (CI 2175, 2721). Log rank tests show significant difference between PPH and SPH (11.8, p=.001), SPH and non PH (18.0, p Wilcoxon tests show statistical significant difference between PPH and SPH (5.1, p=.024) PPH and non PH (9.7, p=.002), SPH and non PH (16.9, p Conclusion PPH survival has worse early survival but better long-term survival. The etiology of scleroderma did not impact survival compared to non-PH. Survival after secondary PH and the outcomes observed may impact risk stratification in certain centers, especially in the setting of challenging regulatory realities.

Response to ‘Screening for Pulmonary Hypertension in Scleroderma’

Response to ‘Screening for Pulmonary Hypertension in Scleroderma’

Screening for Pulmonary Hypertension in Scleroderma

Screening for Pulmonary Hypertension in Scleroderma

Scoring System for Screening of Pulmonary Hypertension in Scleroderma: The Dibosa Study

Scoring System for Screening of Pulmonary Hypertension in Scleroderma: The Dibosa Study

Pulmonary hypertension in scleroderma

Pulmonary hypertension in scleroderma

Biomarkers of pulmonary hypertension in patients with scleroderma: a case-control study.

IntroductionSignificant pulmonary vascular disease is a leading cause of death in patients with scleroderma, and early detection and early medical intervention are important, as they may delay disease progression and improve survival and quality of life. Although several biomarkers have been proposed, there remains a need to define a reliable biomarker of early pulmonary vascular disease and subsequent development of pulmonary hypertension (PH). The purpose of this study was to define potential biomarkers for clinically significant pulmonary vascular disease in patients with scleroderma.MethodsThe circulating growth factors basic fibroblast growth factor, placental growth factor (PlGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor, and soluble VEGF receptor 1 (sFlt-1), as well as cytokines (interleukin [IL]-1β IL-2, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor-α, and interferon-γ), were quantified in patients with scleroderma with PH (n = 37) or without PH (n = 40). In non-parametric unadjusted analyses, we examined associations of growth factor and cytokine levels with PH. In a subset of each group, a second set of earlier samples, drawn 3.0±1.6 years earlier, were assessed to determine the changes over time.ResultssFlt-1 (p = 0.02) and PlGF (p = 0.02) were higher in the PH than in the non-PH group. sFlt-1 (ρ = 0.3245; p = 0.01) positively correlated with right ventricular systolic pressure. Both PlGF (p = 0.03) and sFlt-1 (p = 0.04) positively correlated with the ratio of forced vital capacity to diffusing capacity for carbon monoxide (DLCO), and both inversely correlated with DLCO (p = 0.01). Both PlGF and sFlt-1 levels were stable over time in the control population.ConclusionsOur study demonstrated clear associations between regulators of angiogenesis (sFlt-1 and PlGF) and measures of PH in scleroderma and that these growth factors are potential biomarkers for PH in patients with scleroderma. Larger longitudinal studies are required for validation of our results.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0712-4) contains supplementary material, which is available to authorized users.

Pulmonary Vascular Dimensions as an Indicator of Pulmonary Hypertension in Scleroderma

Pulmonary Vascular Dimensions as an Indicator of Pulmonary Hypertension in Scleroderma

Pulmonary endothelial injury in the context of perturbed transforming growth factor β signalling as a unique model of pulmonary hypertension in scleroderma

BackgroundThe development of pulmonary arterial hypertension in scleroderma remains an important contributor to mortality in this condition, despite substantial improvements in outcomes due to modern therapeutic strategies. No animal models of scleroderma develop this important complication. We describe the constitutive vascular phenotype of a mouse model of scleroderma and show that pulmonary endothelial injury replicates the pathological changes of pulmonary arterial hypertension seen in human disease. MethodsThe TβRIIΔk-fib mouse strain expresses a kinase-deficient type II transforming growth factor β (TGFβ) receptor driven by a fibroblast-specific promoter leading to ligand-dependent upregulation of TGFβ signalling; this mouse strain replicates key fibrotic features of scleroderma. We did structural, biochemical, and functional assessments of pulmonary and systemic vessels, including in-vivo haemodynamic studies, before and after vascular endothelial growth factor receptor (VEGFR) inhibition with SU5416, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ, endothelin, and VEGF signalling axes in vivo; tissue sections; and explanted pulmonary arterial smooth muscle cells. FindingsIn the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly raised pulmonary artery pressures resemble the well-described chronic hypoxia model of pulmonary hypertension. After administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells; the result was right ventricular hypertrophy confirming haemodynamically significant pulmonary arterial hypertension. Altered TGFβ, endothelin, and ligand and receptor expression of VEGF were consistent with a scleroderma phenotype. InterpretationThis study replicates key features of scleroderma-associated pulmonary arterial hypertension in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support functional interplay between TGFβ, endothelin, and VEGF that provides insight into pathogenesis. FundingArthritis Research UK.

Pulmonary hypertension in scleroderma and its relation to disease activity

AimThe aim of this study was to screen for pulmonary hypertension (PH) in scleroderma patients using Doppler echocardiography, and correlate it with inflammatory parameters of the disease.Patients and methodsDoppler echocardiography was performed in 39 patients with scleroderma (three men and 36 women) and was compared with 20 age-matched and sex-matched healthy controls. Fifteen (38.5%) patients had limited scleroderma and 24 (61.5%) patients had diffuse scleroderma. PH was diagnosed if the peak systolic pressure gradient at the tricuspid valve was more than 25 mmHg. All patients were subjected to full assessment of history, rheumatological examination, laboratory studies, chest radiography, and pulmonary function tests.ResultsIn 39 scleroderma patients, PH was detected in five patients (12.8%); four of them had limited scleroderma and one had diffuse scleroderma. The range of pulmonary artery systolic pressure was 37–63 mmHg (mean ± SD = 49.2 ± 10.1). There was a highly statistically significant difference between patients and controls (P< 0.0001). There were no significant differences between patients with and without PH in clinical features, except for arthritis and Raynaud’s phenomena (P < 0.04, 0.01). Significant differences in the level of erythrocyte sedimentation rate, complement, and anticentromere antibodies were found in patients with PH versus those without PH (P < 0.04, <0.03, <0.002, respectively). There was a statistically significant correlation between pulmonary artery pressure with disease duration (P < 0.001) and Valentini Disease Activity Index (P< 0.001).ConclusionPatients with scleroderma have an increased risk of pulmonary arterial hypertension. Echocardiography should be used as a screening tool in patients who are at a higher risk of developing PH.

Erratum to: An Update on the Evaluation and Management of Pulmonary Hypertension in Scleroderma

Erratum to: An Update on the Evaluation and Management of Pulmonary Hypertension in Scleroderma

An Update on the Evaluation and Management of Pulmonary Hypertension in Scleroderma

Pulmonary arterial hypertension associated with scleroderma (SScPAH) is a debilitating, highly lethal condition that responds to an array of therapies. Quality of life and prognosis are substantially improved by treatment, and early diagnosis and treatment are associated with improved outcomes. There are serious limitations to current screening programs. Many more questions need to be addressed. Why is PAH so common in SSc? Why is the tolerance of pulmonary hypertension so poor in scleroderma? What are the best measures of response to therapy in SSc patients with PAH? Should we use different parameters in prognostic scores in SScPAH? Why is postcapillary pulmonary hypertension so common in SSc? How do we reliably differentiate lung disease-associated pulmonary hypertension from PAH? The aim of this review is to summarize the main areas of progress over the past decade and to look to the challenges for the next decade.

Abstract 5656: Anticentromere Antibody Increases ICAM-1 Expression and Monocyte Adhesion in Pulmonary Endothelial Cells: Implications for Scleroderma-Associated Pulmonary Hypertension

BACKGROUND: Scleroderma is characterized by the presence of high circulating levels of anticentromere antibody (ACA) and is commonly complicated by pulmonary hypertension (PHT). We hypothesized that ACA may alter pulmonary endothelial cell function. METHODS: Human pulmonary microvascular endothelial cells (HPMvECs) were treated with ACA (0.25 – 1.0 mg/mL, equivalent to serum titers of 1:320 – 1:2560) and IgG controls. Monocyte adhesion to HPMvECs was measured by automated cell count and cell adhesion molecule expression (ICAM-1 and VCAM-1) was assessed by flow cytometry (protein) and RT-PCR (mRNA). Promoter activity was assessed by luciferase reporter vector in HPMvECs and human umbilical vein endothelial cells (HUVECs). ACA uptake into HPMvECs was assessed by fluorescent microscopy. RESULTS: Fluorescently labeled ACA was shown to penetrate HPMvECs within 10 min. ACA increased ICAM-1 protein levels in a dose-dependent manner (118±11, 132±8 &amp; 162±7% increase vs control (100%) for 0.50, 0.75 &amp; 1.0 mg/mL respectively, P &lt; 0.0001, n=5; Fig ). No effect was observed for VCAM-1. ICAM-1 increases were associated with enhanced monocyte adhesion to endothelial cells (211±9%, 1.0 mg/mL vs control, P &lt; 0.0001, n=3). ICAM-1 mRNA levels were markedly increased by ACA (745±113%, 1.0 mg/mL vs control, P &lt; 0.0001, n=4). ACA did not affect ICAM-1 mRNA stability but increased ICAM-1 promoter activity (136±9% &amp; 148±12%, 1.0 mg/mL vs control for HPMvECs &amp; HUVECs respectively, P &lt; 0.01, n=3). CONCLUSION: ACA increases HPMvECs ICAM-1 expression and monocyte cell adhesion. These findings may implicate a role for ACA in the development of PHT in scleroderma.

Six-Minute Walk Test in Scleroderma-Associated Pulmonary Arterial Hypertension: Are We Counting What Counts?

> Everything that can be counted does not necessarily count; > > Everything that counts cannot necessarily be counted > > —Albert Einstein Systemic scleroderma (SSc) is a multisystem disease with protean manifestations, but pulmonary involvement is the leading cause of mortality. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are 2 serious pulmonary complications of SSc that commonly cause clinical symptoms of dyspnea and exercise intolerance, can be associated with severe functional limitation, and often have a poor prognosis for longterm survival. SSc-associated PAH (SSc-PAH) is a serious disease of progressive pulmonary vascular obliteration characterized by persistent elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Untreated SSc-PAH usually results in right-sided heart failure and high risk of death. The average survival in SSc patients diagnosed with PAH is 1–2 years1–3. Patients with SSc-PAH have a worse prognosis than most other PAH patients, including primary or idiopathic PAH (IPAH)4,5. Many new PAH-specific therapies have been studied and are available for the treatment of patients with SSc-PAH. These include prostacyclin derivatives (intravenous epoprostenol, subcutaneous or intravenous treprostinil), a novel family of oral endothelin receptor antagonists (bosentan, sitaxsentan, and ambrisentan), as well as an oral phosphodiesterase type 5 inhibitor (sildenafil)6. Treatment of PAH patients, including SSc-PAH, with these PAH-specific medications is associated with subjective and objective clinical benefit. Given that PAH is a disease of disturbed pulmonary hemodynamics, reductions in mean PAP and PVR, as well as improved right ventricular (RV) function, as evidenced by increased cardiac output, have been expectations of PAH therapy. However, repeated assessment of pulmonary hemodynamics by invasive rightheart catheterization is not feasible, and not necessarily indicated. Doppler echocardiographic assessment of RV systolic pressure (RVSP) is commonly used as a surrogate for systolic PAP. Moreover, other echo parameters, such … See Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma, page 330 Address reprint requests to Dr. S. Mehta, Division of Respirology, London Health Sciences Center-Victoria Hospital, Room E2.623, Professional Building, 800 Commissioner’s Road East, London, Ontario N6A 5W9, Canada. E-mail: sanjay.mehta{at}lhsc.on.ca

Limitations to the 6-Minute Walk Test in Interstitial Lung Disease and Pulmonary Hypertension in Scleroderma

To determine factors that influence 6-minute walk distance (6MWD) in patients with scleroderma (systemic sclerosis, SSc)-interstitial lung disease (ILD), SSc-pulmonary hypertension (PH), and idiopathic pulmonary fibrosis (IPF). We retrospectively evaluated all patients with SSc or IPF who performed a 6-minute walk test (6MWT) at a university hospital between 1999 and 2003. Chi-square, ANOVA, simple linear regression, and backwards elimination multivariable regressions were performed. Forty-eight consecutive IPF patients with 6MWT were compared to 33 patients with SSc-ILD, 13 with SSc-PH, 19 with both SSc-ILD and SSc-PH (SSc-Both), and 15 with SSc without ILD or PH (SSc-Neither). Mean 6MWD did not differ between groups. Limitations to 6MWT trended toward dyspnea in IPF and lower extremity pain in SSc. SSc-Both had dyspnea limitation more than other SSc subgroups (p = 0.017). Percentage predicted forced vital capacity (FVC%) and percentage predicted carbon monoxide diffusing capacity (DLCO%) were more strongly predictive of 6MWD in IPF than in SSc; however, exclusion of SSc subjects with pain limitation improved the predictive value. Significant correlates of 6MWD in multivariable analysis differed between subgroups. Pain limitations confound the utility of the 6MWT, particularly in SSc. Pain may cause failure to reach a dyspnea limitation during 6MWT, especially in SSc patients without both ILD and PH. Correlates of 6MWD differ between SSc subgroups and IPF; therefore, the 6MWT distance is not always reflective of the same physiological process. 6MWT interpretation should include consideration of vascular, pulmonary, and musculoskeletal exercise limitations.

Isolated pulmonary hypertension in scleroderma

Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival. To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients. Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma. Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT. Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.

Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: insights into the association of specific autoantibodies with distinct disease phenotypes.

To investigate the association of specific autoantibodies with distinct disease phenotypes. The association of autoantibodies to nucleophosmin/B23 with pulmonary hypertension in scleroderma, and the susceptibility of autoantigens to cleavage by granzyme B (GB), provided a focus for these studies. Intact cells were subjected to cytotoxic lymphocyte granule-induced death, and the susceptibility of autoantigens to cleavage by GB was addressed by immunoblotting and/or by a novel immunofluorescence assay. B23 was cleaved efficiently by GB in vitro, but was highly resistant to cleavage by GB during cytotoxic lymphocyte granule-mediated death of many intact cell types. In contrast, this molecule was highly susceptible to GB-mediated proteolysis exclusively in differentiated vascular smooth muscle cells. Topoisomerase I and several other GB substrates did not show this striking change in cleavage susceptibility in different cell types. These data demonstrate that the cleavage of B23 by GB in intact cells is dependent upon both cell type and phenotype. The susceptibility of this autoantigen (which is associated with a distinct pulmonary vascular phenotype in scleroderma) to GB-mediated proteolysis selectively in vascular smooth muscle cells suggests that the GB-cleavable conformation of autoantigens may occur selectively in the target tissue, and may play a role in shaping the phenotype-specific autoimmune response.