Biomarkers for systemic sclerosis - tools for diagnosis and treatment
Ключові слова:
systemic sclerosis, biomarkers, antinuclear antibodies, non-specific autoantibodies, fibrosis, pulmonary hypertension, prognosis.Анотація
Introduction. Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organ fibrosis with prior vascular and immune dysfunction. Depending on the cutaneous fibrosis degree, SSc is divided into two main subtypes: limited skin SSc (LT-SSc) and diffuse skin SSc (DF-SSc). This classification is characterized by association with certain autoantibodies that specifically define these clinical phenotypes. Despite ongoing research, so far only a few biomarkers of SSc have been fully validated, approved and implemented into practice. Material and methods. This paper presents a literature review of promising SSc prognostic biomarkers, biomarkers of disease activity, skin fibrosis and internal organ lesion with the aim of providing comprehensive information on the applicability of biomarkers for research and clinical use. A literature search was conducted in the PubMed, MedLine, Scopus and Embase databases from 2000–2018. Keywords used for search: systemic sclerosis, anti-nuclear autoantibodies, non-specific autoantibodies, biomarkers. Results and discussion. The presence of autoantibodies is the central determining aspect of autoimmune diseases. Autoantibodies are found in the initial diagnosis of more than 95% of SSc patients and associated with different disease subtypes and the clinical course severity. Antitopoisomerase I (ATA), or anti-Scl-70 antibodies, and anticentromere (ACA) antibodies are the most widely used SSC diagnostic biomarkers. ATA is observed mainly in patients with DF-SSc, associated with a worse prognosis, increased mortality, the digital ulcer development, pulmonary fibrosis and heart damage. ACA is detected in 90% of patients with LT-SSc. In patients with Raynaud's phenomenon, ACA predicts the occurrence of LT-SSc. ACA positivity correlates with a more favorable prognosis and lower mortality compared with positivity for other autoantibodies associated with SSc. Antibodies against RNA polymerase III (anti-RNP III) are highly specific for patients with SSc (98–100%). Anti-RNP III is associated with DF-SSc, debut in old age, a renal crisis and a high risk of a malignant tumor developing. Anti-Th/To are clinically associated with LT-SSc and are the marker for the worst survival. Anti-U3RNP is often associated with DF-SSc, the visceral organ involvement, especially kidneys and heart. The presence of UI RNP antibodies is associated not only with SSc, but also with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myositis, many patients have criteria for mixed connective tissue disease. More recently, autoantibodies to type 1 angiotensin II receptor (AT1R) and type A endothelin-1 receptor (ETAR) have been found to be elevated in the serum of most patients with SSc and are associated with vascular and fibrous complications. Relatively rare and less specific antibodies are anti-U11/U12 RNP, PM/Scl antibodies, antibodies against estrogen receptors α, anti-endothelial cell antibodies, anti-fibroblast antibodies, anti-platelet-derived growth factor receptor antibodies. It has been shown that the elevated expression of pro-fibrotic miRNAs and reduced expression of antifibrotic miRNAs are important factors in the developments of fibrosis in SSc. Unlike other autoimmune diseases, such as SLE or RA, for many patients with SSc it is difficult to assess the presence of current inflammation, it is not easy to determine the blood vessel and tissue fibrosis, especially at an early stage of the disease. Biochemical markers candidates for assessing the activity and severity of the disease in SSc were obtained based on the presence of an association with target organ damage. Serum von Willebrand factor, glycoprotein Krebs von den Lungen 6, procollagen-III aminoterminal-propeptide, tissue inhibitor of matrix metalloproteinase-1, IL-6, growth factor differentiation 15, the serum level of cartilage oligomeric matrix protein, angiopoietin/Tie2 and hyaluronic acid showed a significant correlation with both the activity and the severity of the disease. Conclusion. Thus, serum autoantibodies are considered important biomarkers for early and accurate diagnosis of SSc and are associated with distinctive clinical subgroups and various prognostic signs of this disease. It has been demonstrated that some autoantibodies directed against autoantigen specific targets induce inflammation, activate fibroblasts, promote the synthesis and deposition of collagen, and activate endothelial cells, participating in the pathogenesis of SSc. Understanding the pathogenic role of autoantibodies in SSc can help identify new therapeutic targets for this complex disease.
Посилання
Fett N. Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies. // Clin Dermatol. 2013. Vol.31. N4. P.432-437. doi: 10.1016/j.clindermatol.2013.01.010.
Graf SW, Hakendorf P, Lester S [et al.] South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome. // Int J Rheum Dis. 2012. Vol.15. P.102–109. doi:10. 1111/j.1756-185X.2011.01688.x
Henault J, Tremblay M, Clement I, [et al.] Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. // Arthritis Rheum. 2004. Vol.50. P.3265-74. doi: 10.1002/art.20515
Assassi S, Arnett FC, Reveille JD, [et al.] Clinical, immunologic and genetic features of systemic sclerosis. // Arthritis Rheum. 2007. Vol.56. P.2031-7. doi: 10.1002/art.22647
Walker UA, Tyndall A, Czirják L [et al.] Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group database. // Ann Rheum Dis. 2007. Vol. 66. P.754–763. doi:10.1136/ard.2006.062901
Matsushita T, Takehara K. An update on biomarker discovery and use in systemic sclerosis. // Expert Rev Mol Diagn. 2017. Vol.7. N9. P.823-833. doi: 10.1080/14737159.2017.1356722.
Denton CP, Krieg T, Guillevin L [et al.] Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry. // Ann Rheum Dis. 2012. Vol.71. P.718–721. doi:10.1136/annrheumdis-2011-200631
Hamaguchi Y, Fujimoto M, Hasegawa M, [et al.] Re-emergence of anti-topoisomerase I antibody with exacerbated development of skin sclerosis in a patient with systemic sclerosis. // J Am Acad Dermatol. 2010. Vol.62. P.142-4. doi: 10.1016/j.jaad.2009.01.032 63.
Sato H, Lagan AL, Alexopoulou C, [et al.] The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma. // Arthritis Rheum. 2004. Vol.50. P.558-64. doi: 10.1002/art.20065
Koenig M, Dieudé M, Senécal JL. Predictive value of antinuclear autoantibodies: the lessons of the systemic sclerosis autoantibodies. // Autoimmun Rev. 2008. Vol.7. P.588–593. doi:10.1016/j.autrev. 2008.06.010
Miyawaki S, Asanuma H, Nishiyama S, Yoshinaga Y. Clinical and serological heterogeneity in patients with anticentromere antibodies. // J Rheumatol. 2005. Vol.32. P.1488–1494.
Hasegawa M. Biomarkers in systemic sclerosis: Their potential to predict clinical courses. // J Dermatol. 2016. Vol.43. N1. P.29-38. doi: 10.1111/1346-8138.13156.
Cavazzana I, Angela C, Paolo A. [et al.] Anti-RNA polymerase III antibodies: a marker of systemic sclerosis with rapid onset and skin thickening progression. // Autoimmun Rev. 2009. Vol.8. P.580–584. doi: 10.1016/j.autrev.2009.02.002
SteenVD. Autoantibodies in systemic sclerosis. // Semin Arthritis Rheum. 2005. Vol.35. P.35–42. doi: 10.1016 / j.semarthrit.2005.03.005
Esakova O, Krasilnikov AS. Of proteins and RNA: The RNase P/MRP family. // RNA. 2010. Vol.16. N9. P.1725–1747. doi: 10.1261/rna.2214510
Mitri GM, Lucas M, Fertig N. [et al.] A comparison between anti-TH/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement. // Arthritis Rheum. 2003. Vol.48. P.203–209. doi:10.1002/art.10760
Bonella F, Costabel U. Biomarkers in connective tissue disease-associated interstitial lung disease. // Semin Respir Crit Care Med. 2014. Vol.35. N2. P.181-200. doi: 10.1055/s-0034-1371527.
Castelino FV, Varga J. Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development. // Expert Rev Clin Immunol. 2013. Vol.9. N11. P.1077-90. doi: 10.1586/1744666X.2013.848792.
Aggarwal R, Lucas M, Fertig N. [et al.] Anti-U3 RNP autoantibodies in systemic sclerosis. // Arthritis Rheum. 2009. Vol.60. P.1112-8. doi: 10.1002/art.24409
Takeda Y, Dynan WS. Autoantibodies against DNA double strand break repair proteins. // Front Biosci. 2001. Vol.6. P.1412-22. doi:10.2741/Takeda
Franceschini F, Cavazzana I, Generali D. [et al.] Anti-Ku antibodies in connective tissue diseases: clinical and serological evaluation of 14 patients. // J Rheumatol. 2002. Vol.29. P.1393-7
Mehra S, Walker J, Patterson K, Fritzler MJ. Autoantibodies in systemic sclerosis. // Autoimmun Rev. 2013. Vol.12. P.340–54. doi:10.1016/j.autrev. 2012. 05. 011
Rozman B, Cucnik S, Sodin-Semrl S. [et al]. Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study // Ann Rheum Dis. 2008. Vol.67. N9. P.1282-1286. doi: 10.1186/ar3550
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. Vol.190. P.808–817. doi: 10.1164/rccm.201403-0442OC
Kill A, Tabeling C, Undeutsch R. [et al.] Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. // Arthritis Res Ther. 2014. Vol. 16. N1. P. 29. doi: 10.1186/ar4457
Giovannetti A, Maselli A, Colasanti T. [et al.] Autoantibodies to estrogen receptor α in systemic sclerosis (SSc) as pathogenetic determinants and markers of progression. // PLoS One. 2013. Vol.8. N9. P.74332. doi:10.1371/journal.pone.0074332
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 Care Res. 2009. Vol.61. P.958–965. doi:10.1002/art.24586
D’Aoust J, Hudson M, Tatibouet S. [et al.] Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients. // Arthritis Rheum. 2014. Vol.66. N6. P.1608-15. doi: 10.1002/art.38428
Ananyeva LP, Aleksandrova EN. Аutoantibodies in systemic sclerosis: spectrum, clinical associations, and prognostic value. // Rheumatology Science and Practice. 2016. Vol.54. N1. P.86-99. (In Russ.) https://doi.org/10.14412/1995-4484-2016-86-99
Fineschi S, Goffin L, Rezzonico R. [et al.] Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. // Arthritis Rheum. 2008. Vol.58. N12. P.3913-23. doi:10.1002/art.24049
Terrier B, Tamby MC, Camoin L. [et al.] Antifibroblast antibodies from systemic sclerosis patients bind to {alpha}-enolase and are associated with interstitial lung disease. // Ann Rheum Dis. 2010. Vol.69. N2. P.428-33. doi: 10.1136/ard.2008.104299
Corallo C, Franci B, Lucani B. [et al.] From microvasculature to fibroblasts: contribution of antiendothelial cell antibodies in systemic sclerosis. // Int J Immunopathol Pharmacol. 2015. Vol.28. P.93–103.
Laplante P, Raymond MA, Gagnon G. [et al.] Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. // J Immunol. 2005. Vol.174. P.5740-9. doi: 10.4049/jimmunol.174.9.5740
Servettaz A, Tamby MC, Guilpain P. [et al.] Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B). // Clin Immunol. 2006. Vol.120. P.212-9. doi: 10.1016/j.clim.2006.02.006106.
Arends SJ, Damoiseaux JG, Duijvestijn AM. [et al.] Functional implications of IgG anti-endothelial cell antibodies in pulmonary arterial hypertension. // Аutoimmunity. 2013. Vol.46. N7. P.463-70. doi: 10.3109/08916934.2013.812080
Svegliati S, Amico D, Spadoni T. [et al.] Agonistic Anti-PDGF Receptor Autoantibodies from Patients with Systemic Sclerosis Impact Human Pulmonary Artery Smooth Muscle Cells Function In Vitro. // Front Immunol. 2017. Vol.8. P.75. doi: 10.3389/fimmu.2017.00075
Baroni SS, Santillo M, Bevilacqua F. [et al.] Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. // N Engl J Med. 2006. Vol.354. P.2667-76. doi: 10.1056/NEJMoa052955
Iwayama T, Lorin E. Olson Involvement of PDGF in Fibrosis and Scleroderma: Recent Insights from Animal Models and Potential Therapeutic OpportunitiesCurr Rheumatol Rep. // Curr Rheumatol Rep. – 2013. Vol.15. N2. P.304. doi: 10.1007/s11926-012-0304-0
Hammond SM. An overview of microRNAs. // Adv Drug Deliv Rev. 2015. Vol.87. P.3–14. doi: 10.1016/j.addr.2015.05.001
Zhu H, Li Y, Qu S. [et al.] MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma. // J Clin Immunol. 2012. Vol.32. P.514–522. doi:10.1007/s10875-011-9647-y
Honda N, Jinnin M, Kira-Etoh T. [et al.] MiR-150 downregulation contributes to the constitutive type i collagen overexpression in scleroderma dermal fibroblasts via the induction of integrin β3. // Am J Pathol. 2013. Vol.182. P.206–216. doi:10.1016/j.ajpath.2012.09.023
Eissa MG, Artlett CM. The MicroRNA miR-155 Is Essential in Fibrosis. // Noncoding RNA. 2019. Vol.12. P.5. doi: 10.3390/ncrna5010023
Tanaka S, Suto A, Ikeda K. [et al.] Alteration of circulating miRNAs in SSc: miR-30b regulates the expression of PDGF receptor β. // Rheumatology (Oxford). 2013. Vol.52. P.1963–1972. doi:10.1093/rheumatology/ket254
Makino K, JinninM, Hirano A. [et al.] The downregulation of microRNA let-7a contributes to the excessive expression of type I collagen in systemic and localized scleroderma. // J Immunol. 2013. Vol.190. P.3905–3915. doi:10.4049/jimmunol.1200822
Makino K, Jinnin M, Kajihara I. [et al.] Circulating miR-142-3p levels in patients with systemic sclerosis. Clin Exp Dermatol. 2012. Vol.37. P.34–39. doi:10.1111/j.1365-2230.2011.04158.x
Valentini G, Bencivelli W, Bombardieri S. [et al.] European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. // Ann Rheum Dis. 2003. Vol.62. P.901–903. doi:10.1136/ard.62.9.901
Nagy Z, Czirják L. Increased levels of amino terminal propeptide of type III procollagen are an unfavourable predictor of survival in systemic sclerosis. // Clin Exp Rheumatol. 2005. Vol.23. P.165–172.
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. 2014. Vol.73. P.420–427. doi:10.1136/annrheumdis-2012-202843
Barnes T, Gliddon A, Doré CJ, [et al.] Baseline vWF factor predicts the development of elevated pulmonary artery pressure in systemic sclerosis. // Rheumatology (Oxford). 2012. Vol.51. P.1606–1609. doi:10.1093/rheumatology/kes068
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. 2011. Vol.28. P.27–33
Gheita TA, Hussein H. Cartilage oligomeric matrix protein (COMP) in systemic sclerosis (SSc): role in disease severity and subclinical rheumatoid arthritis overlap. // Joint Bone Spine. 2012. Vol.79. P.51–56. doi:10.1016/j.jbspin.2011.02.022
Milam KE, Parikh SM. The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. // Tissue Barriers. 2015. Vol.3. N.1-2. P.957508. doi: 10.4161/21688362.2014.957508.
Dunne JV, Keen KJ, Van Eeden SF. Circulating angiopoietin and Tie-2 levels in systemic sclerosis. // Rheumatol Int. 2013. Vol.33. P.475–484. doi:10.1007/s00296-012-2378-4
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. Vol.40. P.435–446. doi:10.3899/jrheum.120725
Jurisic Z, Martinovic-Kaliterna D, Marasovic-Krstulovic D. [et al.] Relationship between interleukin-6 and cardiac involvement in systemic sclerosis. // Rheumatology (Oxford). 2013. Vol.52. P.1298–1302. doi:10.1093/rheumatology/ket131
Codullo V, Baldwin HM, Singh MD. [et al.] An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis. // Ann Rheum Dis. 2011. Vol.70. P.1115–1121. doi:10.1136/ard.2010.137349
Lambrecht S, Smith V, De Wilde K. [et al.] Growth differentiation factor 15, a marker of lung involvement in systemic sclerosis, is involved in fibrosis development but is not indispensable for fibrosis development. Arthritis Rheum. 2014. Vol.66. P.418–427. doi:10.1002/art.38241
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