Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development

References

• Mayes MD, Lacey Jr JV, Beebe-Dimmer J et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 48(8), 2246–2255 (2003).
   PubMedGoogle Scholar
• Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr. Opin. Rheumatol. 24(2), 165–170 (2012).
   PubMed Web of Science ®Google Scholar
• Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin. Arthritis Rheum. 39(4), 269–277 (2010).
   PubMed Web of Science ®Google Scholar
• Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann. Rheum. Dis. 66(7), 940–944 (2007).
   PubMed Web of Science ®Google Scholar
• Castro SV, Jimenez SA. Biomarkers in systemic sclerosis. Biomark. Med. 4(1), 133–147 (2010).
   PubMed Web of Science ®Google Scholar
• Abignano G, Buch M, Emery P, Del Galdo F. Biomarkers in the management of scleroderma: an update. Curr. Rheumatol. Rep. 13(1), 4–12 (2011).
   Google Scholar
• Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69(3), 89–95 (2001).
   PubMed Web of Science ®Google Scholar
• Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American rheumatism association diagnostic and therapeutic criteria committee. Arthritis Rheum. 23(5), 581–590 (1980).
   PubMedGoogle Scholar
• Lonzetti LS, Joyal F, Raynauld JP et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum. 44(3), 735–736 (2001).
   PubMedGoogle Scholar
• LeRoy EC, Black C, Fleischmajer R et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 15(2), 202–205 (1988).
   PubMed Web of Science ®Google Scholar
• Ferri C, Valentini G, Cozzi F et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 81(2), 139–153 (2002).
   PubMed Web of Science ®Google Scholar
• Scussel-Lonzetti L, Joyal F, Raynauld JP et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore), 81(2), 154–167 (2002).
   PubMed Web of Science ®Google Scholar
• Poormoghim H, Lucas M, Fertig N, Medsger TA, Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. 43(2), 444–451 (2000).
   Web of Science ®Google Scholar
• Steen VD. Autoantibodies in systemic sclerosis. Semin. Arthritis Rheum. 35(1), 35–42 (2005).
   PubMed Web of Science ®Google Scholar
• Ho KT, Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res. Ther. 5(2), 80–93 (2003).
   Google Scholar
• Mahler M, You D, Baron M, Taillefer SS, Hudson M, Fritzler MJ. Anti-centromere antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA. Clin. Chim. Acta. 412 (21–22), 1937–1943 (2011).
   Google Scholar
• Reveille JD, Solomon DH. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum. 49(3), 399–412 (2003).
   PubMedGoogle Scholar
• Hesselstrand R, Scheja A, Shen GQ, Wiik A, Akesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford) 42(4), 534–540 (2003).
   Web of Science ®Google Scholar
• Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J. Dermatol. 37(1), 42–53 (2010).
   PubMed Web of Science ®Google Scholar
• Hu PQ, Fertig N, Medsger TA Jr, Wright TM. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum. 48(5), 1363–1373 (2003).
   PubMedGoogle Scholar
• Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat. Rev. Rheumatol. 6(2), 112–116 (2010).
   PubMed Web of Science ®Google Scholar
• Hanke K, Dahnrich C, Bruckner CS et al. Diagnostic value of anti-topoisomerase I antibodies in a large monocentric cohort. Arthritis Res. Ther. 11(1), R28 (2009).
   Google Scholar
• Nikpour M, Hissaria P, Byron J et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res. Ther. 13(6), R211 (2011).
   PubMed Web of Science ®Google Scholar
• Nguyen B, Assassi S, Arnett FC, Mayes MD. Association of RNA polymerase III antibodies with scleroderma renal crisis. J. Rheumatol. 37(5), 1068; author reply 1069 (2010).
   Web of Science ®Google Scholar
• Cavazzana I, Ceribelli A, Airo P, Zingarelli S, Tincani A, Franceschini F. Anti-RNA polymerase III antibodies: a marker of systemic sclerosis with rapid onset and skin thickening progression. Autoimmun. Rev. 8(7), 580–584 (2009).
   Web of Science ®Google Scholar
• Nihtyanova SI, Parker JC, Black CM, Bunn CC, Denton CP. A longitudinal study of anti-RNA polymerase III antibody levels in systemic sclerosis. Rheumatology (Oxford), 48(10), 1218–1221 (2009).
   Google Scholar
• Graf SW, Hakendorf P, Lester S et al. South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome. Int. J. Rheum. Dis. 15(1), 102–109 (2012).
   PubMed Web of Science ®Google Scholar
• Aggarwal R, Lucas M, Fertig N, Oddis CV, Medsger TA Jr. Anti-U3 RNP autoantibodies in systemic sclerosis. Arthritis Rheum. 60(4), 1112–1118 (2009).
   PubMedGoogle Scholar
• Steen V, Domsic RT, Lucas M, Fertig N, Medsger TA Jr. A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum. 64(9), 2986–2994 (2012).
   PubMedGoogle Scholar
• Fertig N, Domsic RT, Rodriguez-Reyna T et al. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum. 61(7), 958–965 (2009).
   PubMedGoogle Scholar
• Villalta D, Imbastaro T, Di Giovanni S et al. Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis. Autoimmun. Rev. 12(2), 114–120 (2012).
   PubMed Web of Science ®Google Scholar
• Ingegnoli F, Boracchi P, Gualtierotti R et al. Improving outcome prediction of systemic sclerosis from isolated Raynaud's phenomenon: role of autoantibodies and nail-fold capillaroscopy. Rheumatology (Oxford) 49(4), 797–805 (2010).
   PubMed Web of Science ®Google Scholar
• Koenig M, Joyal F, Fritzler MJ et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 58(12), 3902–3912 (2008).
   PubMed Web of Science ®Google Scholar
• Assassi S, Sharif R, Lasky RE et al. Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort. Arthritis Res. Ther. 12(5), R166 (2010).
   PubMed Web of Science ®Google Scholar
• Czirjak L, Foeldvari I, Muller-Ladner U. Skin involvement in systemic sclerosis. Rheumatology (Oxford) 47(Suppl. 5), v44–v45 (2008).
   Web of Science ®Google Scholar
• Czirjak L, Nagy Z, Aringer M, Riemekasten G, Matucci-Cerinic M, Furst DE. The EUSTAR model for teaching and implementing the modified Rodnan skin score in systemic sclerosis. Ann. Rheum. Dis. 66(7), 966–969 (2007).
   Web of Science ®Google Scholar
• Lenga Y, Koh A, Perera AS, McCulloch CA, Sodek J, Zohar R. Osteopontin expression is required for myofibroblast differentiation. Circ. Res. 102(3), 319–327 (2008).
   Web of Science ®Google Scholar
• Wu M, Schneider DJ, Mayes MD et al. Osteopontin in systemic sclerosis and its role in dermal fibrosis. J. Invest. Dermatol. 132(6), 1605–1614 (2012).
   PubMed Web of Science ®Google Scholar
• Lorenzen JM, Kramer R, Meier M et al. Osteopontin in the development of systemic sclerosis--relation to disease activity and organ manifestation. Rheumatology (Oxford) 49(10), 1989–1991 (2010).
   Google Scholar
• Barizzone N, Marchini M, Cappiello F et al. Association of osteopontin regulatory polymorphisms with systemic sclerosis. Hum. Immunol. 72(10), 930–934 (2011).
   PubMed Web of Science ®Google Scholar
• Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat. Rev. Rheumatol. 8(1), 42–54 (2011).
   PubMed Web of Science ®Google Scholar
• Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117(3), 524–529 (2007).
   PubMed Web of Science ®Google Scholar
• Ahrens D, Koch AE, Pope RM, Stein-Picarella M, Niedbala MJ. Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis. Arthritis Rheum. 39(9), 1576–1587 (1996).
   PubMedGoogle Scholar
• Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N. Localization of matrix metalloproteinases-1, −2, and −9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab. Invest. 78(6), 687–698 (1998).
   PubMed Web of Science ®Google Scholar
• Kim WU, Min SY, Cho ML et al. Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res. Ther. 7(1), R71–R79 (2005).
   PubMed Web of Science ®Google Scholar
• Pardo A, Selman M. Matrix metalloproteinases in aberrant fibrotic tissue remodeling. Proc. Am. Thorac. Soc. 3(4), 383–388 (2006).
   PubMedGoogle Scholar
• Serrati S, Cinelli M, Margheri F et al. Systemic sclerosis fibroblasts inhibit in vitro angiogenesis by MMP-12-dependent cleavage of the endothelial cell urokinase receptor. J. Pathol. 210(2), 240–248 (2006).
   Google Scholar
• Manetti M, Guiducci S, Romano E et al. Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage. Ann. Rheum. Dis. 71(6), 1064–1072 (2012).
   PubMed Web of Science ®Google Scholar
• Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem. 77, 289–312 (2008).
   PubMed Web of Science ®Google Scholar
• Wei J, Bhattacharyya S, Varga J. Peroxisome proliferator-activated receptor gamma: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis. Curr. Opin. Rheumatol. 22(6), 671–676 (2010).
   PubMed Web of Science ®Google Scholar
• Wei J, Ghosh AK, Sargent JL et al. PPARgamma downregulation by TGFss in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One 5(11), e13778 (2010).
   PubMed Web of Science ®Google Scholar
• Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol. Sci. 30(5), 234–239 (2009).
   Web of Science ®Google Scholar
• Lakota K, Wei J, Carns M et al. Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker? Arthritis Res. Ther. 14(3), R102 (2012).
   PubMed Web of Science ®Google Scholar
• Arakawa H, Jinnin M, Muchemwa FC et al. Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients. Exp. Dermatol. 20(9), 764–766 (2011).
   PubMed Web of Science ®Google Scholar
• Sargent JL, Whitfield ML. Capturing the heterogeneity in systemic sclerosis with genome-wide expression profiling. Expert Rev. Clin. Immunol. 7(4), 463–473 (2011).
   PubMed Web of Science ®Google Scholar
• Milano A, Pendergrass SA, Sargent JL et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS ONE 3(7), e2696 (2008).
   PubMed Web of Science ®Google Scholar
• Farina G, Lemaire R, Pancari P, Bayle J, Widom RL, Lafyatis R. Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor beta. Ann. Rheum. Dis. 68(3), 435–441 (2009).
   Google Scholar
• Farina G, Lafyatis D, Lemaire R, Lafyatis R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 62(2), 580–588 (2010).
   PubMed Web of Science ®Google Scholar
• Abignano G, Aydin SZ, Castillo-Gallego C et al. Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma. Ann. Rheum. Dis. DOI: 10.1136/annrheumdis-2012-202682 (2013) (Epub ahead of print).
   Google Scholar
• Tyndall AJ, Bannert B, Vonk M et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann. Rheum. Dis. 69(10), 1809–1815 (2010).
   PubMed Web of Science ®Google Scholar
• Wells AU, Steen V, Valentini G. Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology (Oxford), 48 (Suppl. 3), iii40–iii44 (2009).
   Google Scholar
• Behr J, Furst DE. Pulmonary function tests. Rheumatology (Oxford) 47 (Suppl. 5), v65–v67 (2008).
   Google Scholar
• Goh NS, Desai SR, Veeraraghavan S et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am. J. Respir. Crit. Care Med. 177(11), 1248–1254 (2008).
   PubMed Web of Science ®Google Scholar
• Behr J. Approach to the diagnosis of interstitial lung disease. Clin. Chest Med. 33(1), 1–10 (2012).
   PubMed Web of Science ®Google Scholar
• Moore OA, Goh N, Corte T et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford) 52(1), 155–160 (2013).
   PubMed Web of Science ®Google Scholar
• Corvol H, Flamein F, Epaud R, Clement A, Guillot L. Lung alveolar epithelium and interstitial lung disease. Int. J. Biochem. Cell Biol. 41(8–9), 1643–1651 (2009).
   Google Scholar
• Bonella F, Volpe A, Caramaschi P et al. Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis. Vasc. Diffuse Lung Dis. 28(1), 27–33 (2011).
   PubMed Web of Science ®Google Scholar
• Yanaba K, Hasegawa M, Takehara K, Sato S. Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J. Rheumatol. 31(6), 1112–1120 (2004).
   PubMed Web of Science ®Google Scholar
• Hant FN, Ludwicka-Bradley A, Wang HJ et al. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J. Rheumatol. 36(4), 773–780 (2009).
   PubMed Web of Science ®Google Scholar
• Prasse A, Pechkovsky DV, Toews GB et al. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am. J. Respir. Crit. Care Med. 173(7), 781–792 (2006).
   PubMed Web of Science ®Google Scholar
• Kodera M, Hasegawa M, Komura K, Yanaba K, Takehara K, Sato S. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum. 52(9), 2889–2896 (2005).
   PubMed Web of Science ®Google Scholar
• Tiev KP, Hua-Huy T, Kettaneh A et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur. Respir. J. 38(6), 1355–1360 (2011).
   PubMed Web of Science ®Google Scholar
• Elhaj M, Charles J, Pedroza C et al. Can serum surfactant protein d or cc-chemokine ligand 18 predict outcome of interstitial lung disease in patients with early systemic sclerosis? J. Rheumatol. 40(7), 1114–1120 (2013).
   PubMed Web of Science ®Google Scholar
• Lee CG, Da Silva CA, Dela Cruz CS et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Ann. Rev. Physiol. 73, 479–501 (2011).
   PubMed Web of Science ®Google Scholar
• Migliaccio CT, Buford MC, Jessop F, Holian A. The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosis. J. Leukocyte Biol. 83(3), 630–639 (2008).
   PubMed Web of Science ®Google Scholar
• Lee CG, Herzog EL, Ahangari F et al. Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-beta1 signaling. J. Immunol. 189(5), 2635–2644 (2012).
   PubMedGoogle Scholar
• Muangchan C, Harding S, Khimdas S, Bonner A, Baron M, Pope J. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res. (Hoboken), 64(9), 1405–1414 (2012).
   PubMed Web of Science ®Google Scholar
• Liu X, Mayes MD, Pedroza C et al. Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis? Arthritis Care Res. (Hoboken), 65(8), 1375–1380 (2013).
   PubMed Web of Science ®Google Scholar
• 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. Arthritis Rheum. 63(3), 783–794 (2011).
   PubMed Web of Science ®Google Scholar
• Assassi S, Wu M, Tan FK et al. Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis. Arthritis Rheum. () (2013) (Epub ahead of print).
   Google Scholar
• Radstake TR, Gorlova O, Rueda B et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat. Genet. 42(5), 426–429 (2010).
   PubMed Web of Science ®Google Scholar
• Sharif R, Mayes MD, Tan FK et al. IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. Ann Rheum. Dis. 71(7), 1197–1202 (2012).
   Web of Science ®Google Scholar
• Dimitroulas T, Giannakoulas G, Karvounis H, Settas L, Kitas GD. Systemic sclerosis-related pulmonary hypertension: unique characteristics and future treatment targets. Curr. Pharm. Des. 18(11), 1457–1464 (2012).
   PubMed Web of Science ®Google Scholar
• Humbert M, Yaici A, de Groote P et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 63(11), 3522–3530 (2011).
   PubMed Web of Science ®Google Scholar
• Chung L, Liu J, Parsons L et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 138(6), 1383–1394).
   Google Scholar
• Dimitroulas T, Giannakoulas G, Karvounis H, Gatzoulis MA, Settas L. Natriuretic peptides in systemic sclerosis-related pulmonary arterial hypertension. Semin. Arthritis Rheum. 39(4), 278–284 (2010).
   PubMed Web of Science ®Google Scholar
• Galie N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur. Heart J. 30(20), 2493–2537 (2009).
   PubMed Web of Science ®Google Scholar
• Williams MH, Handler CE, Akram R et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur. Heart J. 27(12), 1485–1494 (2006).
   PubMed Web of Science ®Google Scholar
• Cavagna L, Caporali R, Klersy C et al. Comparison of brain natriuretic peptide (BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic sclerosis. J. Rheumatol. 37(10), 2064–2070 (2010).
   PubMed Web of Science ®Google Scholar
• Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF. Hyperuricemia in severe pulmonary hypertension. Chest 117(1), 19–24 (2000).
   PubMed Web of Science ®Google Scholar
• Dimitroulas T, Giannakoulas G, Dimitroula H et al. Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study. Rheumatol. Int. 31(2), 263–267 (2012).
   Google Scholar
• Meadows CA, Risbano MG, Zhang L et al. Increased expression of growth differentiation factor-15 in systemic sclerosis-associated pulmonary arterial hypertension. Chest 139(5), 994–1002 (2011).
   PubMed Web of Science ®Google Scholar
• Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S. Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity. Mod. Rheumatol. 22(5), 668–675 (2012).
   PubMed Web of Science ®Google Scholar
• Lenting PJ, Casari C, Christophe OD, Denis CV. von Willebrand factor: the old, the new and the unknown. J Thromb Haemost, 10(12), 2428–2437 (2012).
   PubMed Web of Science ®Google Scholar
• Barnes T, Gliddon A, Dore CJ, Maddison P, Moots RJ. Baseline vWF factor predicts the development of elevated pulmonary artery pressure in systemic sclerosis. Rheumatology (Oxford) 51(9), 1606–1609 (2012).
   Google Scholar
• van Loon JE, Kavousi M, Leebeek FW et al. von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population. J. Thromb. Haemost. 10(7), 1262–1269 (2012).
   PubMed Web of Science ®Google Scholar
• Shao D, Park JE, Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol. Res. 63(6), 504–511 (2011).
   Google Scholar
• Schmidt J, Launay D, Soudan B et al. [Assessment of plasma endothelin level measurement in systemic sclerosis]. Rev. Med. Interne. 28(6), 371–376 (2007).
   PubMed Web of Science ®Google Scholar
• Cheadle C, Berger AE, Mathai SC et al. Erythroid-specific transcriptional changes in PBMCs from pulmonary hypertension patients. PLoS ONE 7(4), e34951 (2012).
   Web of Science ®Google Scholar
• Pendergrass SA, Hayes E, Farina G et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One 5(8), e12106 (2010).
   PubMed Web of Science ®Google Scholar
• Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 40(11), 1984–1991 (1997).
   PubMed Web of Science ®Google Scholar
• Medsger TA, Jr., Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W. Assessment of disease severity and prognosis. Clin. Exp. Rheumatol. 21(3 Suppl. 29), S42–46 (2003).
   PubMed Web of Science ®Google Scholar
• Abignano G, Cuomo G, Buch MH et al. The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis. Ann. Rheum Dis, (2013) (Epub ahead of print).
   Google Scholar
• Parkes J, Roderick P, Harris S et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut, 59(9), 1245–1251 (2010).
   PubMed Web of Science ®Google Scholar
• Liu X, Mayes MD, Tan FK et al. Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis. Arthritis Rheum. 65(1), 226–235 (2013).
   PubMed Web of Science ®Google Scholar
• Khan K, Xu S, Nihtyanova S et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann. Rheum. Dis. 71(7), 1235–1242 (2012).
   PubMed Web of Science ®Google Scholar
• De Lauretis A, Sestini P, Pantelidis P et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J. Rheumatol. 40(4), 435–446 (2013).
   PubMed Web of Science ®Google Scholar
• Hinchcliff M, Huang CC, Wood TA et al. Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J. Invest. Dermatol. 133(8), 1979–1989 (2013).
   PubMed Web of Science ®Google Scholar
• Chung L, Fiorentino DF, Benbarak MJ et al. Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum. 60(2), 584–591 (2009).
   PubMed Web of Science ®Google Scholar
• Aden N, Shiwen X, Aden D et al. Proteomic analysis of scleroderma lesional skin reveals activated wound healing phenotype of epidermal cell layer. Rheumatology (Oxford) 47(12), 1754–1760 (2008).
   PubMed Web of Science ®Google Scholar
• Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome. Res 19(1), 92–105 (2009).
   PubMed Web of Science ®Google Scholar
• Maurer B, Stanczyk J, Jungel A et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62(6), 1733–1743 (2010).
   PubMed Web of Science ®Google Scholar
• Zhu H, Li Y, Qu S et al. MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma. J. Clin. Immunol. 32(3), 514–522 (2012).
   PubMed Web of Science ®Google Scholar
• Robinson WH, Lindstrom TM, Cheung RK, Sokolove J. Mechanistic biomarkers for clinical decision making in rheumatic diseases. Nat. Rev. Rheumatol. 9(5), 267–276 (2013).
   PubMed Web of Science ®Google Scholar
• van den Hoogen F, Khanna D, Fransen J et al. Classification criteria for systemic sclerosis. Arthritis Rheum. (2013) (In press).
   Google Scholar