An update on biomarker discovery and use in systemic sclerosis

References

• LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol. 1988;15:202–205.
   PubMed Web of Science ®Google Scholar
• Furst DE, Clements PJ. Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol. 1997;24(suppl 48):53–57.
   Google Scholar
• Ligon C, Hummers LK. Biomarkers in scleroderma: progressing from association to clinical utility. Curr Rheumatol Rep. 2016;18(3):17.
   PubMed Web of Science ®Google Scholar
• Hasegawa M. Biomarkers in systemic sclerosis: their potential to predict clinical courses. J Dermatol. 2016;43(1):29–38.
   PubMed Web of Science ®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. 2011;13(6):R211.
   PubMed Web of Science ®Google Scholar
• LeRoy EC, Smith EA, Kahaleh MB, et al. A strategy for determining the pathogenesis of systemic sclerosis: is transforming growth factor b the answer? Arthritis Rheum. 1989;32:817–825.
   PubMed Web of Science ®Google Scholar
• Falanga V, Gerhardt CO, Dasch JR, et al. Skin distribution and differential expression of transforming growth factor beta 1 and beta 2. J Dermatol Sci. 1992;3(3):131–136.
   PubMedGoogle Scholar
• Dantas AT, Goncalves SM, De Almeida AR, et al. Reassessing the role of the active TGF-beta1 as a biomarker in systemic sclerosis: association of serum levels with clinical manifestations. Dis Markers. 2016;2016:6064830.
   PubMed Web of Science ®Google Scholar
• Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007;56(1):323–333.
   PubMed Web of Science ®Google Scholar
• McCormick LL, Zhang Y, Tootell E, et al. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol. 1999;163(10):5693–5699.
   PubMed Web of Science ®Google Scholar
• Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–2807.
   PubMed Web of Science ®Google Scholar
• Mori T, Kawara S, Shinozaki M, et al. Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol. 1999;181(1):153–159.
   PubMed Web of Science ®Google Scholar
• Takehara K. Hypothesis: pathogenesis of systemic sclerosis. J Rheumatol. 2003;30(4):755–759.
   PubMed Web of Science ®Google Scholar
• Sato S, Nagaoka T, Hasegawa M, et al. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol. 2000;27(1):149–154.
   PubMed Web of Science ®Google Scholar
• Kawaguchi Y. IL-1 alpha gene expression and protein production by fibroblasts from patients with systemic sclerosis. Clin Exp Immunol. 1994;97(3):445–450.
   PubMed Web of Science ®Google Scholar
• Maekawa T, Jinnin M, Ohtsuki M, et al. Serum levels of interleukin-1alpha in patients with systemic sclerosis. J Dermatol. 2013;40(2):98–101.
   PubMed Web of Science ®Google Scholar
• Manetti M, Guiducci S, Ceccarelli C, et al. Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement. Ann Rheum Dis. 2011;70(10):1876–1878.
   PubMed Web of Science ®Google Scholar
• Yanaba K, Yoshizaki A, Asano Y, et al. Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Clin Rheumatol. 2011;30(6):825–830.
   PubMed Web of Science ®Google Scholar
• Wagner A, Kohm M, Nordin A, et al. Increased serum levels of the IL-33 neutralizing sST2 in limited cutaneous systemic sclerosis. Scand J Immunol. 2015;82(3):269–274.
   PubMed Web of Science ®Google Scholar
• Rice LM, Mantero JC, Stifano G, et al. A proteome-derived longitudinal pharmacodynamic biomarker for diffuse systemic sclerosis skin. J Invest Dermatol. 2017;137(1):62–70.
   PubMed Web of Science ®Google Scholar
• Majewski S, Wojas-Pelc A, Malejczyk M, et al. Serum levels of soluble TNF alpha receptor type I and the severity of systemic sclerosis. Acta Derm Venereol. 1999;79(3):207–210.
   PubMed Web of Science ®Google Scholar
• Gruschwitz MS, Albrecht M, Vieth G, et al. In situ expression and serum levels of tumor necrosis factor-alpha receptors in patients with early stages of systemic sclerosis. J Rheumatol. 1997;24(10):1936–1943.
   PubMed Web of Science ®Google Scholar
• Bossini-Castillo L, Broen JC, Simeon CP, et al. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort. Ann Rheum Dis. 2011;70(4):638–641.
   PubMed Web of Science ®Google Scholar
• Coustet B, Bouaziz M, Dieude P, et al. Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis. J Rheumatol. 2012;39(5):997–1003.
   PubMed Web of Science ®Google Scholar
• Gourh P, Arnett FC, Tan FK, et al. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann Rheum Dis. 2010;69(3):550–555.
   PubMed Web of Science ®Google Scholar
• Komura K, Yoshizaki A, Kodera M, et al. Increased serum soluble OX40 in patients with systemic sclerosis. J Rheumatol. 2008;35(12):2359–2362.
   PubMed Web of Science ®Google Scholar
• Elhai M, Avouac J, Hoffmann-Vold AM, et al. OX40L blockade protects against inflammation-driven fibrosis. Proc Natl Acad Sci U S A. 2016;113(27):E3901–10.
   PubMed Web of Science ®Google Scholar
• Horikawa M, Hasegawa M, Komura K, et al. Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity. J Invest Dermatol. 2005;125(4):731–737.
   PubMed Web of Science ®Google Scholar
• Matsushita Y, Hasegawa M, Matsushita T, et al. Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice. J Immunol. 2007;179(1):698–707.
   PubMed Web of Science ®Google Scholar
• Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–3964.
   PubMed Web of Science ®Google Scholar
• Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012;52:199–219.
   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. 2012;71(7):1235–1242.
   PubMed Web of Science ®Google Scholar
• Sato S, Hasegawa M, Takehara K. Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci. 2001;27:140–146.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Fujimoto M, Hasegawa M, et al. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127(12):2772–2780.
   PubMed Web of Science ®Google Scholar
• Saito E, Fujimoto M, Hasegawa M, et al. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002;109(11):1453–1462.
   PubMed Web of Science ®Google Scholar
• Le Huu D, Matsushita T, Jin G, et al. IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. J Invest Dermatol. 2012;132(12):2752–2761.
   PubMed Web of Science ®Google Scholar
• Kitaba S, Murota H, Terao M, et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol. 2012;180(1):165–176.
   PubMed Web of Science ®Google Scholar
• Desallais L, Avouac J, Frechet M, et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis. Arthritis Res Ther. 2014;16(4):R157.
   PubMed Web of Science ®Google Scholar
• Khanna D, Distler J, Sandner P, et al. Emerging strategies for treatment of systemic sclerosis. J Scleroderma Relat Disord. 2016;1(2):186–193.
   Web of Science ®Google Scholar
• Shima Y, Kuwahara Y, Murota H, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology. 2010;49(12):2408–2412.
   PubMed Web of Science ®Google Scholar
• Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–2640.
   PubMed Web of Science ®Google Scholar
• Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285(5425):260–263.
   PubMed Web of Science ®Google Scholar
• Cheema GS, Roschke V, Hilbert DM, et al. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44(6):1313–1319.
   PubMed Web of Science ®Google Scholar
• Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109(1):59–68.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Hasegawa M, Yanaba K, et al. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192–201. .
   PubMed Web of Science ®Google Scholar
• Matsushita T, Fujimoto M, Hasegawa M, et al. Elevated serum APRIL levels in patients with systemic sclerosis: distinct profiles of systemic sclerosis categorized by APRIL and BAFF. J Rheumatol. 2007;34(10):2056–2062.
   PubMed Web of Science ®Google Scholar
• Wutte N, Kovacs G, Berghold A, et al. CXCL13 and B-cell activating factor as putative biomarkers in systemic sclerosis. Br J Dermatol. 2013;169(3):723–725.
   PubMed Web of Science ®Google Scholar
• Bosello S, De Santis M, Lama G, et al. B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther. 2010;12(2):R54.
   PubMed Web of Science ®Google Scholar
• Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–12324.
   PubMed Web of Science ®Google Scholar
• Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009;60(2):578–583.
   PubMed Web of Science ®Google Scholar
• Lafyatis R, O’Hara C, Feghali-Bostwick CA, et al. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum. 2007;56(9):3167–3168.
   PubMed Web of Science ®Google Scholar
• Sato S, Hasegawa M, Fujimoto M, et al. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–6643.
   PubMed Web of Science ®Google Scholar
• Fujimoto M, Fujimoto Y, Poe JC, et al. CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity. 2000;13(1):47–57.
   PubMed Web of Science ®Google Scholar
• Tsuchiya N, Kuroki K, Fujimoto M, et al. Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis. Arthritis Rheum. 2004;50(12):4002–4007.
   PubMed Web of Science ®Google Scholar
• Sato S, Fujimoto M, Hasegawa M, et al. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–1927.
   PubMed Web of Science ®Google Scholar
• Hitomi Y, Tsuchiya N, Hasegawa M, et al. Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis. Tissue Antigens. 2007;69(3):242–249.
   PubMedGoogle Scholar
• Poe JC, Smith SH, Haas KM, et al. Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice. PloS One. 2011;6(7):e22464.
   PubMed Web of Science ®Google Scholar
• Komura K, Fujimoto M, Matsushita T, et al. Increased serum soluble CD40 levels in patients with systemic sclerosis. J Rheumatol. 2007;34(2):353–358.
   PubMed Web of Science ®Google Scholar
• Komura K, Fujimoto M, Yanaba K, et al. Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse. Ann Rheum Dis. 2008;67(6):867–872.
   PubMed Web of Science ®Google Scholar
• Edwards JCW, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol. 2006;6(5):394–403.
   PubMed Web of Science ®Google Scholar
• Smith V, van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis. 2010;69(1):193–197.
   PubMed Web of Science ®Google Scholar
• Smith V, Piette Y, van Praet JT, et al. Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol. 2013;40(1):52–57.
   PubMed Web of Science ®Google Scholar
• Daoussis D, Liossis SNC, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology. 2010;49(2):271–280.
   PubMed Web of Science ®Google Scholar
• Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S17–22.
   PubMed Web of Science ®Google Scholar
• Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2014;74(6):1188-1194.
   Google Scholar
• Tedder TF, Matsushita T. Regulatory B cells that produce IL-10: a breath of fresh air in allergic airway disease. J Allergy Clin Immunol. 2010;125(5):1125–1127.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Yanaba K, Bouaziz JD, et al. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Investig. 2008;118(10):3420–3430.
   PubMed Web of Science ®Google Scholar
• Evans JG, Chavez-Rueda KA, Eddaoudi A, et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol. 2007;178(12):7868–7878.
   PubMed Web of Science ®Google Scholar
• Yanaba K, Bouaziz JD, Haas KM, et al. A regulatory B cell subset with a unique CD1d(hi)CD5(+) phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28(5):639–650.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Le Huu D, Kobayashi T, et al. A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation. J Allergy Clin Immunol. 2016;138(4):1170–82e9.
   PubMed Web of Science ®Google Scholar
• Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–541.
   PubMed Web of Science ®Google Scholar
• Blair PA, Norena LY, Flores-Borja F, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–140.
   PubMed Web of Science ®Google Scholar
• Le Huu D, Matsushita T, Jin G, et al. Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease. Blood. 2013;121(16):3274–3283.
   PubMed Web of Science ®Google Scholar
• Mavropoulos A, Simopoulou T, Varna A, et al. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494–504.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Hamaguchi Y, Hasegawa M, et al. Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology. 2015;55(2):263-267.
   PubMed Web of Science ®Google Scholar
• Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222–233.
   PubMed Web of Science ®Google Scholar
• Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215–1226.
   PubMed Web of Science ®Google Scholar
• Matsushima K, Larsen CG, DuBois GC, et al. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med. 1989;169(4):1485–1490.
   PubMed Web of Science ®Google Scholar
• Saito Y, Hasegawa M, Fujimoto M, et al. The loss of MCP-1 attenuates cutaneous ischemia-reperfusion injury in a mouse model of pressure ulcer. J Invest Dermatol. 2008;128(7):1838–1851.
   PubMed Web of Science ®Google Scholar
• Yalcinkaya Y, Cinar S, Artim-Esen B, et al. The relationship between vascular biomarkers and disease characteristics in systemic sclerosis: elevated MCP-1 is predominantly associated with fibrotic manifestations. Clin Exp Rheumatol. 2016;34(5):S110–S4.
   PubMed Web of Science ®Google Scholar
• Hasegawa M, Fujimoto M, Matsushita T, et al. Serum chemokine and cytokine levels as indicators of disease activity in patients with systemic sclerosis. Clin Rheumatol. 2011;30(2):231–237.
   PubMed Web of Science ®Google Scholar
• van Bon L, Affandi AJ, Broen J, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014;370(5):433–443.
   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. 2013;65(1):226–235.
   PubMed Web of Science ®Google Scholar
• Mondini M, Vidali M, De Andrea M, et al. A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cutaneous systemic sclerosis: the interferon-inducible gene IFI16. Arthritis Rheum. 2006;54(12):3939–3944.
   PubMed Web of Science ®Google Scholar
• Costa S, Mondini M, Caneparo V, et al. Detection of anti-IFI16 antibodies by ELISA: clinical and serological associations in systemic sclerosis. Rheumatology. 2011;50(4):674–681.
   PubMed Web of Science ®Google Scholar
• Fang F, Liu L, Yang Y, et al. The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy. Arthritis Res Ther. 2012;14(5):R229.
   PubMed Web of Science ®Google Scholar
• Masui Y, Asano Y, Shibata S, et al. Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis. J Eur Acad Dermatol Venereol. 2012;26(3):354–360.
   PubMed 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. 2012;14(3):R102.
   PubMed Web of Science ®Google Scholar
• Marangoni RG, Korman BD, Wei J, et al. Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol. 2015;67(4):1062–1073.
   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. 2010;12(5):R166.
   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. 2013;40(4):435–446.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Fujimoto M, Echigo T, et al. Elevated serum levels of APRIL, but not BAFF, in patients with atopic dermatitis. Exp Dermatol. 2008;17(3):197–202.
   PubMed Web of Science ®Google Scholar
• Bielecki M, Kowal K, Lapinska A, et al. Increased production of a proliferation-inducing ligand (APRIL) by peripheral blood mononuclear cells is associated with antitopoisomerase I antibody and more severe disease in systemic sclerosis. J Rheumatol. 2010;37(11):2286–2289.
   PubMed Web of Science ®Google Scholar
• Carulli MT, Ong VH, Ponticos M, et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum. 2005;52(12):3772–3782.
   PubMed Web of Science ®Google Scholar
• Antonelli A, Ferri C, Fallahi P, et al. CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis–a longitudinal study. Rheumatology. 2008;47(1):45–49.
   PubMed Web of Science ®Google Scholar
• Luzina IG, Atamas SP, Wise R, et al. Gene expression in bronchoalveolar lavage cells from scleroderma patients. Am J Respir Cell Mol Biol. 2002;26(5):549–557.
   PubMed Web of Science ®Google Scholar
• Schmidt K, Martinez-Gamboa L, Meier S, et al. Bronchoalveolar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther. 2009;11(4):R111.
   PubMed Web of Science ®Google Scholar
• Volkmann ER, Tashkin DP, Roth MD, et al. Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease. Arthritis Res Ther. 2016;18(1):305.
   PubMed Web of Science ®Google Scholar
• Hieshima K, Imai T, Baba M, et al. A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes. J Immunol. 1997;159(3):1140–1149.
   PubMed Web of Science ®Google Scholar
• Kodera M, Hasegawa M, Komura K, et al. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis. Arthritis Rheum. 2005;52(9):2889–2896.
   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. 2011;38(6):1355–1360.
   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. 2013;40(7):1114–1120.
   PubMed Web of Science ®Google Scholar
• Schupp J, Becker M, Guenther J, et al. Serum CCL18 is predictive for lung disease progression and mortality in systemic sclerosis. Eur Respir J. 2014;43(5):1530–1532.
   PubMed Web of Science ®Google Scholar
• Chora I, Guiducci S, Manetti M, et al. Vascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis. Autoimmun Rev. 2015;14(4):314–322.
   PubMed Web of Science ®Google Scholar
• Distler O, Del Rosso A, Giacomelli R, et al. Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res. 2002;4(6):R11.
   PubMedGoogle Scholar
• Papaioannou AI, Zakynthinos E, Kostikas K, et al. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis. BMC Pulm Med. 2009;9:18.
   PubMedGoogle Scholar
• Choi JJ, Min DJ, Cho ML, et al. Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol. 2003;30(7):1529–1533.
   PubMed Web of Science ®Google Scholar
• Viac J, Schmitt D, Claudy A. Plasma vascular endothelial growth factor levels in scleroderma are not correlated with disease activity. Acta Derm Venereol. 2000;80(5):383.
   PubMed Web of Science ®Google Scholar
• Maurer B, Distler A, Suliman YA, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis. 2014;73(10):1880–1887.
   PubMed Web of Science ®Google Scholar
• Avouac J, Wipff J, Goldman O, et al. Angiogenesis in systemic sclerosis: impaired expression of vascular endothelial growth factor receptor 1 in endothelial progenitor-derived cells under hypoxic conditions. Arthritis Rheum. 2008;58(11):3550–3561.
   PubMed Web of Science ®Google Scholar
• Silva I, Almeida J, Vasconcelos C. A PRISMA-driven systematic review for predictive risk factors of digital ulcers in systemic sclerosis patients. Autoimmun Rev. 2015;14(2):140–152.
   PubMed Web of Science ®Google Scholar
• Manetti M, Guiducci S, Romano E, et al. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ Res. 2011;109(3):e14–26.
   PubMed Web of Science ®Google Scholar
• Manetti M, Guiducci S, Romano E, et al. Increased plasma levels of the VEGF165b splice variant are associated with the severity of nailfold capillary loss in systemic sclerosis. Ann Rheum Dis. 2013;72(8):1425–1427.
   PubMed Web of Science ®Google Scholar
• Romano E, Chora I, Manetti M, et al. Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis. Ann Rheum Dis. 2016;75(8):1541–1549.
   PubMed Web of Science ®Google Scholar
• Wipff J, Avouac J, Borderie D, et al. Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin. Rheumatology. 2008;47(7):972–975.
   PubMed Web of Science ®Google Scholar
• Cossu M, Andracco R, Santaniello A, et al. Serum levels of vascular dysfunction markers reflect disease severity and stage in systemic sclerosis patients. Rheumatology. 2016;55(6):1112–1116.
   PubMed Web of Science ®Google Scholar
• Avouac J, Meune C, Ruiz B, et al. Angiogenic biomarkers predict the occurrence of digital ulcers in systemic sclerosis. Ann Rheum Dis. 2012;71(3):394–399.
   PubMed Web of Science ®Google Scholar
• Manetti M, Ibba-Manneschi L, Liakouli V, et al. The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Ann Rheum Dis. 2010;69(3):598–605.
   PubMed Web of Science ®Google Scholar
• Terras S, Opitz E, Moritz RKC, et al. Increased serum IL-33 levels may indicate vascular involvement in systemic sclerosis. Ann Rheum Dis. 2013;72(1):144–145.
   PubMed Web of Science ®Google Scholar
• Mazzotta C, Romano E, Bruni C, et al. Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis. Arthritis Res Ther. 2015;17.
   PubMed Web of Science ®Google Scholar
• Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940–944.
   PubMed Web of Science ®Google Scholar
• Hachulla E, Carpentier P, Gressin V, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinerAIR-Sclerodermie study. Rheumatology. 2009;48(3):304–308.
   PubMed Web of Science ®Google Scholar
• Coghlan JG, Denton CP, Grunig E, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340–1349.
   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. 2010;37(10):2064–2070.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum. 2003;48(12):3503–3508.
   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. 2006;27(12):1485–1494.
   PubMed Web of Science ®Google Scholar
• Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516–522.
   PubMed Web of Science ®Google Scholar
• Avouac J, Meune C, Chenevier-Gobeaux C, et al. Cardiac biomarkers in systemic sclerosis: contribution of high-sensitivity cardiac troponin in addition to N-terminal pro-brain natriuretic peptide. Arthritis Care Res (Hoboken). 2015;67(7):1022–1030.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Borderie D, Avouac J, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum. 2008;58(1):284–291.
   PubMed Web of Science ®Google Scholar
• Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–415.
   PubMed Web of Science ®Google Scholar
• Braun-Moscovici Y, Nahir AM, Balbir-Gurman A. Endothelin and pulmonary arterial hypertension. Semin Arthritis Rheum. 2004;34(1):442–453.
   PubMed Web of Science ®Google Scholar
• McLaughlin V, Humbert M, Coghlan G, et al. Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology. 2009;48:25–31.
   Web of Science ®Google Scholar
• Schmidt J, Launay D, Soudan B, et al. Assessment of plasma endothelin level measurement in systemic sclerosis. Rev Med Interne. 2007;28(6):371–376.
   PubMed Web of Science ®Google Scholar
• Ciurzynski M, Bienias P, Irzyk K, et al. Serum endothelin-1 and NT-proBNP, but not ADMA, endoglin and TIMP-1 levels, reflect impaired right ventricular function in patients with systemic sclerosis. Clin Rheumatol. 2014;33(1):83–89.
   PubMed Web of Science ®Google Scholar
• Becker MO, Kill A, Kutsche M, et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med. 2014;190(7):808–817.
   PubMed Web of Science ®Google Scholar
• Avouac J, Riemekasten G, Meune C, et al. Autoantibodies against endothelin 1 type A receptor are strong predictors of digital ulcers in systemic sclerosis. J Rheumatol. 2015;42(10):1801–1807.
   PubMed Web of Science ®Google Scholar
• Abu-Shakra M, Guillemin F, Lee P. Gastrointestinal manifestations of systemic sclerosis. Semin Arthritis Rheum. 1994;24(1):29–39.
   PubMed Web of Science ®Google Scholar
• Ingraham KM, O’Brien MS, Shenin M, et al. Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors. J Rheumatol. 2010;37(3):603–607.
   PubMed Web of Science ®Google Scholar
• Ghrenassia E, Avouac J, Khanna D, et al. Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case-control study. J Rheumatol. 2014;41(1):99–105.
   PubMed Web of Science ®Google Scholar
• Lazzaroni MG, Cavazzana I, Colombo E, et al. Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis: analysis of the EULAR scleroderma trials and research cohort and possible recommendations for screening. J Rheumatol. 2017;44(5):639–647.
   PubMed Web of Science ®Google Scholar
• Shah AA, Rosen A, Hummers L, et al. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum. 2010;62(9):2787–2795.
   PubMed Web of Science ®Google Scholar
• Saigusa R, Asano Y, Nakamura K, et al. Association of anti-RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis. J Dermatol. 2015;42(5):524–527.
   PubMed Web of Science ®Google Scholar
• Airo P, Ceribelli A, Cavazzana I, et al. Malignancies in Italian patients with systemic sclerosis positive for anti-RNA polymerase III antibodies. J Rheumatol. 2011;38(7):1329–1334.
   PubMed Web of Science ®Google Scholar
• Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2014;343(6167):152–157.
   PubMed Web of Science ®Google Scholar
• Manetti M. Emerging biomarkers in systemic sclerosis. Curr Opin Rheumatol. 2016;28(6):606–612.
   PubMed Web of Science ®Google Scholar