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Published in: Rheumatology International 9/2009

01-06-2009 | Original Article

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

Authors: Paola Coral-Alvarado, Gerardo Quintana, Maria Fernanda Garces, Libia Alexandra Cepeda, Jorge Eduardo Caminos, Federico Rondon, Antonio Iglesias-Gamarra, Jose Felix Restrepo

Published in: Rheumatology International | Issue 9/2009

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Abstract

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.
Literature
1.
go back to reference LeRoy EC, Black C, Fleischmajer R et al (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15:202–205PubMed LeRoy EC, Black C, Fleischmajer R et al (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15:202–205PubMed
2.
go back to reference Kahaleh MB (1992) The role of vascular endothelium in fibroblast activation and tissue fibrosis, particularly in scleroderma (systemic sclerosis) and pachydermoperiostosis (primary hypertrophic osteoarthropathy). Clin Exp Rheumatol 10(Suppl 7):51–56PubMed Kahaleh MB (1992) The role of vascular endothelium in fibroblast activation and tissue fibrosis, particularly in scleroderma (systemic sclerosis) and pachydermoperiostosis (primary hypertrophic osteoarthropathy). Clin Exp Rheumatol 10(Suppl 7):51–56PubMed
3.
go back to reference Block JASW (2001) Raynaud’s phenomenon. Lancet 23:20–28 Block JASW (2001) Raynaud’s phenomenon. Lancet 23:20–28
7.
go back to reference Wigley FMLJ, Mayes M, McLain D et al (2005) The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists. Arthritis Rheum 52:2125–2132. doi:10.1002/art.21131 PubMedCrossRef Wigley FMLJ, Mayes M, McLain D et al (2005) The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists. Arthritis Rheum 52:2125–2132. doi:10.​1002/​art.​21131 PubMedCrossRef
8.
go back to reference British Cardiac Society Guidelines (2001) Recommendations on the management of pulmonary hypertension in clinical practice. Heart 86(Suppl):I1–I13 British Cardiac Society Guidelines (2001) Recommendations on the management of pulmonary hypertension in clinical practice. Heart 86(Suppl):I1–I13
9.
go back to reference Vancheeswaran R, Magoulas T, Efrat G et al (1994) Circulating endothelin-1 levels in systemic sclerosis subsets-a marker of fibrosis or vascular dysfunction? J Rheumatol 21:1838–1844PubMed Vancheeswaran R, Magoulas T, Efrat G et al (1994) Circulating endothelin-1 levels in systemic sclerosis subsets-a marker of fibrosis or vascular dysfunction? J Rheumatol 21:1838–1844PubMed
10.
go back to reference Cambrey AD, Harrison NK, Dawes KE et al (1994) Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 11:439–445PubMed Cambrey AD, Harrison NK, Dawes KE et al (1994) Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 11:439–445PubMed
11.
go back to reference Morelli S, Ferri C, Di Francesco L et al (1995) Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension. Ann Rheum Dis 54:730–734PubMedCrossRef Morelli S, Ferri C, Di Francesco L et al (1995) Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension. Ann Rheum Dis 54:730–734PubMedCrossRef
13.
go back to reference Yamane K, Miyauchi T, Suzuki N et al (1992) Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 19:1566–1571PubMed Yamane K, Miyauchi T, Suzuki N et al (1992) Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 19:1566–1571PubMed
15.
go back to reference Venkatesan NRP, Ludwing MS (2002) Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta (1) and interferon-gamma. Am J Physiol Lung Cell Mol Physiol 283:L806–L814PubMed Venkatesan NRP, Ludwing MS (2002) Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta (1) and interferon-gamma. Am J Physiol Lung Cell Mol Physiol 283:L806–L814PubMed
21.
go back to reference Sambo P, Baroni SS, Luchetti M et al (2001) Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 44:2653–2664. doi:10.1002/1529-0131(200111)44:11<;2653::AID-ART445>;3.0.CO;2-1PubMedCrossRef Sambo P, Baroni SS, Luchetti M et al (2001) Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 44:2653–2664. doi:10.1002/1529-0131(200111)44:11<;2653::AID-ART445>;3.0.CO;2-1PubMedCrossRef
25.
go back to reference Kadono T, Kikuchi K, Ihn H et al (1998) Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts. J Rheumatol 25:296–301PubMed Kadono T, Kikuchi K, Ihn H et al (1998) Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts. J Rheumatol 25:296–301PubMed
26.
go back to reference Koch AE, Kronfeld-Harrington LB, Szekanecz Z et al (1993) In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology 61:239–246PubMedCrossRef Koch AE, Kronfeld-Harrington LB, Szekanecz Z et al (1993) In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology 61:239–246PubMedCrossRef
28.
go back to reference Burrows FJDE, Tazzari PL, Amlot P et al (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634PubMed Burrows FJDE, Tazzari PL, Amlot P et al (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634PubMed
32.
go back to reference Leask A, Abraham DJ, Finlay DR et al (2002) Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 46:1857–1865. doi:10.1002/art.10333 PubMedCrossRef Leask A, Abraham DJ, Finlay DR et al (2002) Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 46:1857–1865. doi:10.​1002/​art.​10333 PubMedCrossRef
33.
go back to reference Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic, Therapeutic Criteria Committee (1980) Arthritis and Rheum 23:581–590CrossRef Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic, Therapeutic Criteria Committee (1980) Arthritis and Rheum 23:581–590CrossRef
35.
36.
go back to reference Clements PJ, Lachenbruch PA, Seibold JR et al (1993) Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 20:1892–1896PubMed Clements PJ, Lachenbruch PA, Seibold JR et al (1993) Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 20:1892–1896PubMed
37.
go back to reference Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S (2005) Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol 24:111–116. doi:10.1007/s10067-004-0987-3 PubMedCrossRef Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S (2005) Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol 24:111–116. doi:10.​1007/​s10067-004-0987-3 PubMedCrossRef
38.
go back to reference Southcott AM, Jones KP, Li D et al (1995) Interleukin-8. Differential expression in lone fibrosing alveolitis and systemic sclerosis. Am J Respir Crit Care Med 151:1604–1612PubMed Southcott AM, Jones KP, Li D et al (1995) Interleukin-8. Differential expression in lone fibrosing alveolitis and systemic sclerosis. Am J Respir Crit Care Med 151:1604–1612PubMed
39.
go back to reference Crestani B, Seta N, Palazzo E et al (1994) Interleukin-8 and neutrophils in systemic sclerosis with lung involvement. Am J Respir Crit Care Med 150:1363–1367PubMed Crestani B, Seta N, Palazzo E et al (1994) Interleukin-8 and neutrophils in systemic sclerosis with lung involvement. Am J Respir Crit Care Med 150:1363–1367PubMed
40.
go back to reference Furuse S, Fujii H, Kaburagi Y et al (2003) Serum concentrations of the CXC chemokines interleukin 8 and growth-regulated oncogene-alpha are elevated in patients with systemic sclerosis. J Rheumatol 30:1524–1528PubMed Furuse S, Fujii H, Kaburagi Y et al (2003) Serum concentrations of the CXC chemokines interleukin 8 and growth-regulated oncogene-alpha are elevated in patients with systemic sclerosis. J Rheumatol 30:1524–1528PubMed
41.
go back to reference Hasegawa M, Fujimoto M, Kikuchi K et al (1997) Elevated serum tumor necrosis factor-alpha levels in patients with systemic sclerosis: association with pulmonary fibrosis. J Rheumatol 24:663–665PubMed Hasegawa M, Fujimoto M, Kikuchi K et al (1997) Elevated serum tumor necrosis factor-alpha levels in patients with systemic sclerosis: association with pulmonary fibrosis. J Rheumatol 24:663–665PubMed
43.
go back to reference Meloni F, Caporali R, Marone Bianco A et al (2004) BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 21:111–118PubMed Meloni F, Caporali R, Marone Bianco A et al (2004) BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 21:111–118PubMed
45.
go back to reference Hussein MR, Hassan HI, Hofny ER et al (2005) Alterations of mononuclear inflammatory cells, CD4/CD8 + T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol 58:178–184. doi:10.1136/jcp.2004.019224 PubMedCrossRef Hussein MR, Hassan HI, Hofny ER et al (2005) Alterations of mononuclear inflammatory cells, CD4/CD8 + T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol 58:178–184. doi:10.​1136/​jcp.​2004.​019224 PubMedCrossRef
46.
go back to reference Fujimoto M, Hasegawa M, Hamaguchi Y et al (2006) A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology 213:88–92. doi:10.1159/000093846 PubMedCrossRef Fujimoto M, Hasegawa M, Hamaguchi Y et al (2006) A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology 213:88–92. doi:10.​1159/​000093846 PubMedCrossRef
47.
go back to reference Snowden N, Coupes B, Herrick A et al (1994) Plasma TGF beta in systemic sclerosis: a cross-sectional study. Ann Rheum Dis 53:763–767PubMedCrossRef Snowden N, Coupes B, Herrick A et al (1994) Plasma TGF beta in systemic sclerosis: a cross-sectional study. Ann Rheum Dis 53:763–767PubMedCrossRef
48.
go back to reference Dziadzio M, Smith RE, Abraham DJ et al (2005) Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 44:1518–1524. doi:10.1093/rheumatology/kei088 CrossRef Dziadzio M, Smith RE, Abraham DJ et al (2005) Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 44:1518–1524. doi:10.​1093/​rheumatology/​kei088 CrossRef
49.
go back to reference Ludwicka A, Ohba T, Trojanowska M et al (1995) Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol 22:1876–1883PubMed Ludwicka A, Ohba T, Trojanowska M et al (1995) Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol 22:1876–1883PubMed
Metadata
Title
Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis
Authors
Paola Coral-Alvarado
Gerardo Quintana
Maria Fernanda Garces
Libia Alexandra Cepeda
Jorge Eduardo Caminos
Federico Rondon
Antonio Iglesias-Gamarra
Jose Felix Restrepo
Publication date
01-06-2009
Publisher
Springer-Verlag
Published in
Rheumatology International / Issue 9/2009
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-008-0829-8

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