Top

Published in:

01-03-2019 | Observational Research

Circulating S100 proteins effectively discriminate SLE patients from healthy controls: a cross-sectional study

Authors: Barbora Šumová, Lucie Andrés Cerezo, Lenka Szczuková, Lucie Nekvindová, Michal Uher, Hana Hulejová, Radka Moravcová, Mariam Grigorian, Karel Pavelka, Jiří Vencovský, Ladislav Šenolt, Jakub Závada

Published in: Rheumatology International | Issue 3/2019

Abstract

S100 proteins are currently being investigated as potential diagnostic and prognostic biomarkers of several cancers and inflammatory diseases. The aims of this study were to analyse the plasma levels of S100A4, S100A8/9 and S100A12 in patients with incomplete systemic lupus erythematosus (iSLE), in patients with established SLE and in healthy controls (HCs) and to investigate the potential utility of the S100 proteins as diagnostic or activity-specific biomarkers in SLE. Plasma levels were measured by ELISA in a cross-sectional cohort study of 44 patients with SLE, 8 patients with iSLE and 43 HCs. Disease activity was assessed using the SLEDAI-2K. The mean levels of all S100 proteins were significantly higher in SLE patients compared to HCs. In iSLE patients, the levels of S100A4 and S100A12 but not S100A8/9 were also significantly higher compared to HCs. There were no significant differences in S100 levels between the iSLE and SLE patients. Plasma S100 proteins levels effectively discriminated between SLE patients and HCs. The area under the curve (AUC) for S100A4, S100A8/9 and S100A12 plasma levels was 0.989 (95% CI 0.976–1.000), 0.678 (95% CI 0.563–0.792) and 0.807 (95% CI 0.715–0.899), respectively. S100 levels did not differentiate between patients with high and low disease activity. Only the S100A12 levels were significantly associated with SLEDAI-2K and with cSLEDAI-2K. S100 proteins were significantly higher in SLE patients compared HCs and particularly S100A4 could be proposed as a potential diagnostic biomarker for SLE.

Lisnevskaia L, Murphy G, Isenberg D (2014) Systemic lupus erythematosus. Lancet 384:1878–1888. https://doi.org/10.1016/S0140-6736(14)60128-8 CrossRefPubMed

Ahearn JM, Liu C-C, Kao AH, Manzi S (2012) Biomarkers for systemic lupus erythematosus. Transl Res 159:326–342. https://doi.org/10.1016/j.trsl.2012.01.021 CrossRefPubMed

Tektonidou MG, Ward MM (2011) Validation of new biomarkers in systemic autoimmune diseases. Nat Rev Rheumatol 7:708–717. https://doi.org/10.1038/nrrheum.2011.157 CrossRefPubMedPubMedCentral

Aletaha D, Smolen J The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 23:S100-8

Herbst R, Liu Z, Jallal B, Yao Y (2012) Biomarkers for systemic lupus erythematosus. Int J Rheum Dis 15:433–444. https://doi.org/10.1111/j.1756-185X.2012.01764.x CrossRefPubMed

Sedaghat F, Notopoulos A (2008) S100 protein family and its application in clinical practice. Hippokratia 12:198–204. https://doi.org/10.1016/j.amjsurg.2009.11.010 CrossRefPubMedPubMedCentral

Bresnick AR, Weber DJ, Zimmer DB (2015) S100 proteins in cancer. Nat Rev Cancer 15:96–109. https://doi.org/10.1038/nrc3893 CrossRefPubMedPubMedCentral

Chen H (2014) S100 protein family in human cancer. Am J Cancer Res 4:89–115. https://doi.org/10.1053/j.jvca.2004.07.027 CrossRefPubMedPubMedCentral

Nordal H, Brun J, Hordvik M et al (2016) Calprotectin (S100A8/A9) and S100A12 are associated with measures of disease activity in a longitudinal study of patients with rheumatoid arthritis treated with infliximab. Scand J Rheumatol 45:274–281. https://doi.org/10.3109/03009742.2015.1107128 CrossRefPubMed

10.

Andrés Cerezo L, Mann H, Pecha O et al (2011) Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis Res Ther 13:R122. https://doi.org/10.1186/ar3426 CrossRefPubMedPubMedCentral

11.

Klingelhöfer J, Šenolt L, Baslund B et al (2007) Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: Putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheumatol 56:779–789. https://doi.org/10.1002/ART.22398 CrossRef

12.

Šenolt L, Andres Cerezo L, Šumová B et al (2015) High levels of metastasis-inducing S100A4 protein and treatment outcome in early rheumatoid arthritis: data from the PERAC cohort. Biomarkers 20:47–51. https://doi.org/10.3109/1354750X.2014.989544 CrossRefPubMed

13.

Pleštilová L, Mann H, Andrés Cerezo L et al (2014) The metastasis promoting protein S100A4 levels associate with disease activity rather than cancer development in patients with idiopathic inflammatory myopathies. Arthritis Res Ther 16:468. https://doi.org/10.1186/s13075-014-0468-2 CrossRefPubMedPubMedCentral

14.

Foell D, Roth J (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 50:3762–3771. https://doi.org/10.1002/art.20631 CrossRefPubMed

15.

Foell D, Wittkowski H, Vogl T, Roth J (2006) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81:28–37. https://doi.org/10.1189/jlb.0306170 CrossRefPubMed

16.

Bian L, Strzyz P, Jonsson IM et al (2011) S100a4 deficiency is associated with efficient bacterial clearance and protects against joint destruction during staphylococcal infection. J Infect Dis 204:722–730. https://doi.org/10.1093/infdis/jir369 CrossRefPubMed

17.

Donato R, Cannon BR, Sorci G et al (2013) Functions of S100 proteins. Curr Mol Med 13:24–57. https://doi.org/10.2174/1566524011307010024 CrossRefPubMedPubMedCentral

18.

Andrés Cerezo L, Remá ková M, Tomčik M et al (2014) The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatol (United Kingdom) 53:1520–1526. https://doi.org/10.1093/rheumatology/keu031 CrossRef

19.

Tomcik M, Palumbo-Zerr K, Zerr P et al (2014) S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2013-204516 CrossRefPubMed

20.

Schneider M, Hansen JL, Sheikh SP (2008) S100A4: a common mediator of epithelial–mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med 86:507–522. https://doi.org/10.1007/s00109-007-0301-3 CrossRefPubMed

21.

Soyfoo MS, Roth J, Vogl T et al (2009) Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus. J Rheumatol 36:2190–2194. https://doi.org/10.3899/jrheum.01302 CrossRefPubMed

22.

Tyden H, Lood C, Gullstrand B et al (2013) Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus. Rheumatology 52:2048–2055. https://doi.org/10.1093/rheumatology/ket263 CrossRefPubMed

23.

Turnier JL, Fall N, Thornton S et al (2017) Urine S100 proteins as potential biomarkers of lupus nephritis activity. Arthritis Res Ther 19:242. https://doi.org/10.1186/s13075-017-1444-4 CrossRefPubMedPubMedCentral

24.

Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725. https://doi.org/10.1002/1529-0131(199709)40:9%3C1725::AID-ART29%3E3.0.CO;2-Y CrossRefPubMed

25.

Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291PubMed

26.

Abrahamowicz M, Fortin PR, Du Berger R et al (1998) The relationship between disease activity and expert physician’s decision to start major treatment in active systemic lupus erythematosus: a decision aid for development of entry criteria for clinical trials. J Rheumatol 25:277–284PubMed

27.

Zibert JR, Skov L, Thyssen JP et al (2009) Significance of the S100A4 protein in psoriasis. J Invest Dermatol 130:150–160. https://doi.org/10.1038/jid.2009.206 CrossRef

28.

Fei F, Qu J, Zhang M et al (2017) S100A4 in cancer progression and metastasis: a systematic review. Oncotarget 8:73219–73239. https://doi.org/10.18632/oncotarget.18016 CrossRefPubMedPubMedCentral

29.

Lozano S, Mossad E (2004) Cerebral function monitors during pediatric cardiac surgery: can they make a difference? J Cardiothorac Vasc Anesth 18:645–656. https://doi.org/10.1053/j.jvca.2004.07.027 CrossRefPubMed

30.

Grigorian MS, Tulchinsky EM, Zain S et al (1993) The mts1 gene and control of tumor metastasis. Gene 135:229–238. https://doi.org/10.1016/0378-1119(93)90070-J CrossRefPubMed

31.

Okada H, Danoff TM, Kalluri R, Neilson EG (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273:F563–F574CrossRefPubMed

32.

Grigorian M, Andresen S, Tulchinsky E et al (2001) Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276:22699–22708. https://doi.org/10.1074/jbc.M010231200 CrossRefPubMed

33.

Orre LM, Panizza E, Kaminskyy VO et al (2013) S100A4 interacts with p53 in the nucleus and promotes p53 degradation. Oncogene 32:5531–5540. https://doi.org/10.1038/onc.2013.213 CrossRefPubMed

34.

Li ZH, Bresnick AR (2006) The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA. Cancer Res doi. https://doi.org/10.1158/0008-5472.CAN-05-3087 CrossRef

35.

Xu H, Li M, Zhou Y et al (2016) S100A4 participates in epithelial-mesenchymal transition in breast cancer via targeting MMP2. Tumor Biol 37:2925–2932. https://doi.org/10.1007/s13277-015-3709-3 CrossRef

36.

Davies BR, O’Donnell M, Durkan GC et al (2002) Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer. J Pathol 196:292–299. https://doi.org/10.1002/path.1051 CrossRefPubMed

37.

Hemandas AK, Salto-Tellez M, Maricar SH et al (2006) Metastasis-associated protein S100A4—a potential prognostic marker for colorectal cancer. J Surg Oncol 93:498–503. https://doi.org/10.1002/jso.20460 CrossRefPubMed

38.

Chow K-H, Park HJ, George J et al (2017) S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Res 77:5360–5373. https://doi.org/10.1158/0008-5472.CAN-17-1294 CrossRefPubMedPubMedCentral

39.

Haga HJ, Brun JG, Berntzen HB et al (1993) Calprotectin in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity. Lupus 2:47–50. https://doi.org/10.1177/096120339300200108 CrossRefPubMed

40.

Lood C, Tydén H, Gullstrand B et al (2016) Platelet-derived S100A8/A9 and cardiovascular disease in systemic lupus erythematosus. Arthritis Rheumatol 68:1970–1980. https://doi.org/10.1002/art.39656 CrossRefPubMed

41.

Tantivitayakul P, Benjachat T, Somparn P et al (2016) Elevated expressions of myeloid-related proteins-8 and -14 are danger biomarkers for lupus nephritis. Lupus 25:38–45. https://doi.org/10.1177/0961203315598015 CrossRefPubMed

42.

Hakkim A, Fürnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 107:9813–9818. https://doi.org/10.1073/pnas.0909927107 CrossRefPubMedPubMedCentral

43.

Ren Y, Tang J, Mok MY et al (2003) Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 48:2888–2897. https://doi.org/10.1002/art.11237 CrossRefPubMed

44.

Muñoz LE, Janko C, Franz S et al (2012) Immune complex formation after exposure of autoantigens on the surface of secondary necrotic cells (SNEC) promotes inflammation in SLE. Ann Rheum Dis 71:A73.1–A73. https://doi.org/10.1136/annrheumdis-2011-201238.2 CrossRef

45.

Donnelly S, Roake W, Brown S et al (2006) Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum 54:1543–1556. https://doi.org/10.1002/art.21783 CrossRefPubMed

46.

Cappione A, Anolik JH, Pugh-Bernard A et al (2005) Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest 115:3205–3216. https://doi.org/10.1172/JCI24179 CrossRefPubMedPubMedCentral

47.

Kalaaji M, Mortensen E, Jørgensen L et al (2006) Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am J Pathol 168:1779–1792. https://doi.org/10.2353/ajpath.2006.051329 CrossRefPubMedPubMedCentral

48.

Uccellini MB, Avalos AM, Marshak-Rothstein A, Viglianti GA (2009) Toll-like receptor-dependent immune complex activation of B cells and dendritic cells. Humana Press, Totowa, pp 363–380

49.

Lood C, Stenström M, Tydén H et al (2011) Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus. Arthritis Res Ther 13:R60. https://doi.org/10.1186/ar3314 CrossRefPubMedPubMedCentral

50.

Ghosh HS, Cisse B, Bunin A et al (2010) Continuous expression of the transcription factor E2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 33:905–916. https://doi.org/10.1016/j.immuni.2010.11.023 CrossRefPubMedPubMedCentral

51.

Bianchi ME (2006) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5. https://doi.org/10.1189/jlb.0306164 CrossRefPubMed

52.

Ghavami S, Eshragi M, Ande SR et al (2010) S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res 20:314–331. https://doi.org/10.1038/cr.2009.129 CrossRefPubMed

53.

Gestermann N, Di Domizio J, Lande R et al (2018) Netting neutrophils activate autoreactive B cells in lupus. J Immunol 200:3364–3371. https://doi.org/10.4049/jimmunol.1700778 CrossRefPubMed

54.

Villanueva E, Yalavarthi S, Berthier CC et al (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552. https://doi.org/10.4049/jimmunol.1100450 CrossRefPubMed

55.

Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535. https://doi.org/10.1126/science.1092385 CrossRefPubMed

56.

Lande R, Ganguly D, Facchinetti V et al (2012) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Sci Transl Med 3:1–20. https://doi.org/10.1126/scitranslmed.3001180.Neutrophils CrossRef

57.

Garcia-Romo GS, Caielli S, Vega B et al (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20. https://doi.org/10.1126/scitranslmed.3001201 CrossRefPubMedPubMedCentral

58.

Hakkim A, Furnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci 107:9813–9818. https://doi.org/10.1073/pnas.0909927107 CrossRefPubMedPubMedCentral

59.

Urban CF, Ermert D, Schmid M et al (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5:e1000639. https://doi.org/10.1371/journal.ppat.1000639 CrossRefPubMedPubMedCentral

60.

Richardson BC, Yung RL, Johnson KJ et al (1996) Monocyte apoptosis in patients with active lupus. Arthritis Rheum 39:1432–1434CrossRefPubMed

Title: Circulating S100 proteins effectively discriminate SLE patients from healthy controls: a cross-sectional study
Authors: Barbora Šumová
Lucie Andrés Cerezo
Lenka Szczuková
Lucie Nekvindová
Michal Uher
Hana Hulejová
Radka Moravcová
Mariam Grigorian
Karel Pavelka
Jiří Vencovský
Ladislav Šenolt
Jakub Závada
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Published in: Rheumatology International / Issue 3/2019
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI: https://doi.org/10.1007/s00296-018-4190-2

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2019

Self-reported disease severity in women with systemic lupus erythematosus

Persistence with biological drugs in patients treated in rheumatology practices in Germany

Reliability of real-world data

Challenges in the treatment of fibrodysplasia ossificans progressiva

Secular trends in the incidence and prevalence of rheumatoid arthritis within members of an integrated health care delivery system

Efficacy and safety of long-term treatment with intravenous colchicine for familial Mediterranean fever (FMF) refractory to oral colchicine

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage