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Deshwal H, Weinstein T, Sulica R. Advances in the management of pulmonary arterial hypertension. J Investig Med 2021; 69:1270-1280. [PMID: 34580123 PMCID: PMC8485135 DOI: 10.1136/jim-2021-002027] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2021] [Indexed: 12/13/2022]
Abstract
The management of pulmonary arterial hypertension (PAH) has significantly evolved over the last decades in the wake of more sensitive diagnostics and specialized clinical programs that can provide focused medical care. In the current era of PAH care, 1-year survival rates have increased to 86%–90% from 65% in the 1980s, and average long-term survival has increased to 6 years from 2.8 years. The heterogeneity in the etiology and disease course has opened doors to focusing research in phenotyping the disease and understanding the pathophysiology at a cellular and genetic level. This may eventually lead to precision medicine and the development of medications that may prevent or reverse pulmonary vascular remodeling. With more insight, clinical trial designs and primary end-points may change to identify the true survival benefit of pharmacotherapy. Identifying responders from non-responders to therapy may help provide individualized patient-centered care rather than an algorithm-based approach. The purpose of this review is to highlight the latest advances in screening, diagnosis, and management of PAH.
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Affiliation(s)
- Himanshu Deshwal
- Pulmonary, Sleep and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Tatiana Weinstein
- Pulmonary, Sleep and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Roxana Sulica
- Pulmonary, Sleep and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, USA
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Kolstad KD, Li S, Steen V, Chung L. Long-Term Outcomes in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS). Chest 2018; 154:862-871. [PMID: 29777655 DOI: 10.1016/j.chest.2018.05.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 04/26/2018] [Accepted: 05/01/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH. METHODS Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of patients with SSc at high risk for or with incident pulmonary hypertension from right heart catheterization. Incident World Health Organization group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate Cox regression models identified predictors of mortality. RESULTS Survival in 160 patients with incident SSc-PAH at 1, 3, 5, and 8 years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths from PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Men (hazard ratio [HR], 3.11; 95% CI, 1.38-6.98), diffuse disease (HR, 2.12; 95% CI, 1.13-3.93), systolic pulmonary artery pressure (PAP) on ECG (HR, 1.06 95% CI, 1.01-1.11), mean PAP on right heart catheterization (HR, 1.03; 95% CI, 1.001-1.07), 6-min walk distance (HR, 0.92; 95% CI, 0.86-0.99), and diffusing capacity for carbon monoxide (HR, 0.65; 95% CI, 0.46-0.92) significantly affected survival on multivariate analysis. CONCLUSIONS Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than one-half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.
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Affiliation(s)
- Kathleen D Kolstad
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA
| | - Shufeng Li
- Department of Dermatology, Stanford University School of Medicine, Palo Alto, CA
| | - Virginia Steen
- Division of Rheumatology, Georgetown University Medical Center, Washington, DC
| | - Lorinda Chung
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA; Division of Rheumatology, Department of Medicine, Palo Alto VA Health Care System, Palo Alto, CA.
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Very Early Systemic Sclerosis and Pre-systemic Sclerosis: Definition, Recognition, Clinical Relevance and Future Directions. Curr Rheumatol Rep 2017; 19:65. [PMID: 28921059 DOI: 10.1007/s11926-017-0684-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW The approach to systemic sclerosis (SSc) has changed over the years with an increasing focus on the very early diagnosis of the disease. The terminology identifying patients in the early phase of SSc has been significantly confusing in the last three decades. The purpose of this article is to analyze how the concept of "very early SSc" has evolved over the years, which is the role of an early diagnosis and how early treat patients. RECENT FINDINGS Several attempts have been made over time, to create more sensitive and specific classification criteria to include the largest number of SSc patients, also in the earliest phase. An algorythm for the very early diagnosis of SSc was identified, diagnostic preliminary criteria proposed, and new 2013 ACR/EULAR SSc classification criteria published, including new items and adding emphasis to the vasculopathic manifestations. True biomarkers that could predict the disease evolution are still missing. Treat or not to treat patients in the earliest phases still remain a dilemma. For the moment, the only feasible clinical strategy in very early SSc remains a tight follow up program to detect in "real time" the early internal organ involvement which may allow an aggressive therapeutic agenda.
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Yoon SY, Yoo ES, Yoo EJ, Jung JY, Kim HA, Suh CH. Pulmonary Arterial Hypertension is Normalized Following Six Years of Inhaled Iloprost Treatment in a Patient with Systemic Sclerosis. JOURNAL OF RHEUMATIC DISEASES 2017. [DOI: 10.4078/jrd.2017.24.2.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- So-Young Yoon
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Eun-Soo Yoo
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Eun-Jung Yoo
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Ju-Yang Jung
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Hyoun-Ah Kim
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
| | - Chang-Hee Suh
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
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Misra DP, Chowdhury AC, Phatak S, Agarwal V. Scleroderma: Not an orphan disease any more. World J Rheumatol 2015; 5:131-141. [DOI: 10.5499/wjr.v5.i3.131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/24/2015] [Accepted: 07/14/2015] [Indexed: 02/06/2023] Open
Abstract
Scleroderma (or systemic sclerosis) is a rare disease associated with significant morbidity and mortality. Although previously thought to have a uniformly poor prognosis, the outlook has changed in recent years. We review recent insights into the pathogenesis, clinical features, assessment and management of scleroderma.
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Lambova S. Cardiac manifestations in systemic sclerosis. World J Cardiol 2014; 6:993-1005. [PMID: 25276300 PMCID: PMC4176808 DOI: 10.4330/wjc.v6.i9.993] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 05/11/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
Primary cardiac involvement, which develops as a direct consequence of systemic sclerosis (SSc), may manifest as myocardial damage, fibrosis of the conduction system, pericardial and, less frequently, as valvular disease. In addition, cardiac complications in SSc may develop as a secondary phenomenon due to pulmonary arterial hypertension and kidney pathology. The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of the diversity of cardiac manifestations, the presence of subclinical periods, the type of diagnostic tools applied, and the diversity of patient populations. When clinically manifested, cardiac involvement is thought to be an important prognostic factor. Profound microvascular disease is a pathognomonic feature of SSc, as both vasospasm and structural alterations are present. Such alterations are thought to predict macrovascular atherosclerosis over time. There are contradictory reports regarding the prevalence of atherosclerosis in SSc. According to some authors, the prevalence of atherosclerosis of the large epicardial coronary arteries is similar to that of the general population, in contrast with other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the level of inflammation in SSc is inferior. Thus, the atherosclerotic process may not be as aggressive and not easily detectable in smaller studies. Echocardiography (especially tissue Doppler imaging), single-photon emission computed tomography, magnetic resonance imaging and cardiac computed tomography are sensitive techniques for earlier detection of both structural and functional scleroderma-related cardiac pathologies. Screening for subclinical cardiac involvement via modern, sensitive tools provides an opportunity for early diagnosis and treatment, which is of crucial importance for a positive outcome.
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Ahmed S, Palevsky HI. Pulmonary Arterial Hypertension Related to Connective Tissue Disease. Rheum Dis Clin North Am 2014; 40:103-24. [DOI: 10.1016/j.rdc.2013.10.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Gómez Carrera L, Bonilla Hernan G. Pulmonary manifestations of collagen diseases. Arch Bronconeumol 2013; 49:249-60. [PMID: 23683373 DOI: 10.1016/j.arbres.2012.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Revised: 11/18/2012] [Accepted: 11/20/2012] [Indexed: 10/27/2022]
Abstract
Collagen diseases are a large group of systemic inflammatory diseases of autoimmune etiology. The etiopathogenesis of collagen diseases is multifactorial. There is genetic susceptibility, as many connective tissue disorders show family history, and environmental factors may trigger the disease. Collagen diseases can affect almost all the organs of the body. The respiratory system is one of the most frequently affected, although the prevalence of pulmonary disease is not precisely known for the different collagen disorders. Any structure of the respiratory tract can be affected, but perhaps the most frequent is pulmonary parenchymal disease in the form of pneumonitis, which can be produced in any of the idiopathic interstitial pneumonitis patterns. The pleura, pulmonary vessels, airways and respiratory muscles may also be affected. The frequency of lung disease associated with collagen diseases is on the rise. This due in part to the better diagnostic methods that are available to us today (such as high-resolution computed tomography) and also to the appearance of new forms of pneumonitis associated with the new treatments that are currently used. The objective of this article is to offer a global vision of how collagen diseases can affect the lungs according to the latest scientific evidence.
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Affiliation(s)
- Luis Gómez Carrera
- Servicio de Neumología, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
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Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. ACTA ACUST UNITED AC 2013; 63:783-94. [PMID: 21360508 DOI: 10.1002/art.30159] [Citation(s) in RCA: 173] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Pulmonary complications, including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality in patients with systemic sclerosis (SSc). The aim of this study was to compare the molecular fingerprint of lung tissue and matching primary fibroblasts from patients with SSc with that of lung tissue and fibroblasts from normal donors, patients with idiopathic pulmonary fibrosis (IPF), and patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS Lung tissue samples were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, and patients with IPAH. Microarray data were analyzed using efficiency analysis for determination of the optimal data-processing methods. Real-time polymerase chain reaction and immunohistochemistry were used to confirm differential levels of messenger RNA and protein, respectively. RESULTS Consensus efficiency analysis identified 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. SSc-PF and IPF lungs shared enriched functional groups in genes implicated in fibrosis, insulin-like growth factor signaling, and caveolin-mediated endocytosis. Gene functional groups shared by SSc-PAH and IPAH lungs included those involved in antigen presentation, chemokine activity, and interleukin-17 signaling. CONCLUSION Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts from patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease specific (SSc) and phenotype specific (PF versus PAH). These signatures provide new insights into the pathogenesis and potential therapeutic targets of SSc-related lung disease.
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Affiliation(s)
- Eileen Hsu
- University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Scleroderma-systemic sclerosis. Clin Immunol 2013. [DOI: 10.1016/b978-0-7234-3691-1.00068-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Dimitroulas T, Mavrogeni S, Kitas GD. Imaging modalities for the diagnosis of pulmonary hypertension in systemic sclerosis. Nat Rev Rheumatol 2012; 8:203-13. [DOI: 10.1038/nrrheum.2012.2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Almeida I, Faria R, Vita P, Vasconcelos C. Systemic sclerosis refractory disease: from the skin to the heart. Autoimmun Rev 2011; 10:693-701. [PMID: 21575745 DOI: 10.1016/j.autrev.2011.04.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Systemic sclerosis or scleroderma (SSc) is an heterogeneous disease involving the connective tissue and the microvasculature with fibrosis and vascular occlusion. It is difficult to define refractory SSc once it is itself a paradigm of a refractory condition: there is no evidence of when to act to stop the progression to fibrosis and irreversible microvascular damage. There is no definition of refractory disease in SSc and to propose a definition we used mainly the Medsger severity index and the EULAR 2009 treatment recommendations from the skin to the heart through peripheral vascular, musculoskeletal, gastrointestinal, renal, pulmonary hypertension and interstitial lung disease. We used some clinical setting reflecting the different reasoning when there is probable refractory disease and finally we briefly pointed out some available treatment options to refractory disease. With this reflection, we would like to open paths to a broader discussion.
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Affiliation(s)
- Isabel Almeida
- Unidade de Imunologia Clínica, Hospital de Santo António, Centro Hospitalar do Porto, Portugal.
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Abstract
Systemic sclerosis (SSc) is commonly complicated by pulmonary arterial hypertension (PAH), which is a leading cause of death in the SSc patient population. Owing to the fact that the risk of developing pulmonary hypertension is high, screening is important, although the optimal modality remains to be defined. Furthermore, despite recent advances in therapy for PAH, the response to these interventions in patients with PAH with SSc has been discouraging. The lack of clinical response to these therapies may merely reflect the limitations of traditionally employed PAH outcome measures in SSc-PAH patients or highlight the heterogeneity of the disease manifestations within SSc. Importantly, since extrapulmonary involvement of the GI tract and kidneys by SSc limit candidacy for lung transplantation, new therapies that target abnormal cellular proliferation in the pulmonary vasculature are currently under investigation and may be particularly relevant to SSc-PAH.
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Affiliation(s)
- Stephen C Mathai
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Paul M Hassoun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Pankey EA, Epps M, Nossaman BD, Hyman AL, Kadowitz PJ. Pulmonary Arterial Hypertension-A Deadly Complication of Systemic Sclerosis. JOURNAL OF CLINICAL RHEUMATOLOGY & MUSCULOSKELETAL MEDICINE 2010; 1:11-20. [PMID: 23626904 PMCID: PMC3636503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Moreover, when PAH occurs in patients diagnosed with systemic sclerosis, worse outcomes are observed. The purpose of this review is to discuss the etiologies of PAH found in the systemic sclerosis patient, limitations of current medical therapies, and, finally, potential therapies for patients with this combination.
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Affiliation(s)
- Edward A Pankey
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew Epps
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bobby D Nossaman
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Anesthesiology, Ochsner Clinic Foundation, New Orleans, LA, USA
| | - Albert L Hyman
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Philip J Kadowitz
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
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Chatterjee S. Pulmonary hypertension in systemic sclerosis. Semin Arthritis Rheum 2010; 41:19-37. [PMID: 21047671 DOI: 10.1016/j.semarthrit.2010.08.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Revised: 07/04/2010] [Accepted: 08/18/2010] [Indexed: 11/19/2022]
Abstract
OBJECTIVES To discuss the clinical subtypes, pathogenesis, pathology, diagnostic evaluation, treatment options, and prognosis of pulmonary hypertension in systemic sclerosis (SSc-PH) and highlight its fundamental differences from idiopathic pulmonary arterial hypertension (IPAH). METHODS A Medline search for articles published between January 1969 and June 2010 was conducted using the following keywords: scleroderma, systemic sclerosis, pulmonary hypertension, pulmonary arterial hypertension, pulmonary veno-occlusive disease, pathogenesis, pathology, investigation, treatment, and prognosis. The essential differences from IPAH in pathogenesis and histopathologic findings were highlighted and the limitations of some of the investigations used were emphasized. The differences in response to currently accepted therapy and prognosis were also reviewed. RESULTS In scleroderma, pulmonary hypertension can be present in isolation or along with interstitial lung disease and left heart disease. In SSc-PH, the unique histopathologic findings in the lungs include intimal fibrosis, absence of plexiform lesions, and a high prevalence of pulmonary veno-occlusive disease-like lesions. Both "6-minute walk test" and NT-proBNP have their limitations in the evaluation of SSc-PH. For treatment, calcium channel blockers are ineffective and anticoagulation should be used with caution. Currently approved therapies are not as effective and prognosis is much worse in SSc-PH compared with IPAH. CONCLUSIONS SSc-PH is a complex condition with poorer response to therapy and worse outcome compared with that of IPAH. Recent findings have shed some light about the pathophysiology and pathogenesis of SSc-PH. Further research in this area is warranted to better understand the complex pathogenesis and devise better therapeutic strategies.
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Affiliation(s)
- Soumya Chatterjee
- Department of Rheumatic and Immunologic Diseases, Orthopedic and Rheumatology Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
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Current world literature. Curr Opin Rheumatol 2010; 22:704-12. [PMID: 20881793 DOI: 10.1097/bor.0b013e3283404094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Pulmonary arterial hypertension in systemic sclerosis. Autoimmun Rev 2010; 9:761-70. [PMID: 20601197 DOI: 10.1016/j.autrev.2010.06.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Accepted: 06/13/2010] [Indexed: 12/16/2022]
Abstract
Pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is a complex clinical situation resulting from restricted flow through the pulmonary arterial circulation ending in increased pulmonary vascular resistance and right heart failure. PAH is a common and life-threatening complication in connective tissue diseases, specifically in SSc if not treated rapidly and adequately. Based on the emerging knowledge in SSc epidemiology by large scale patient cohorts such as EUSTAR, of PAH pathophysiology and advances in cardiopulmonary diagnostic techniques, several novel treatment approaches have been examined and have proceeded to licensing and daily use in the clinical practice. Amongst them are different endothelin receptor antagonists and PDE-5 inhibitors, but several other ideas are being currently pursued to improve the long-term outcome of the affected patients.
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