INTRODUCTION: The aim of this study was to examine whether circulating levels of the proinflammatory glycoprotein tenascin-C (TNC) are useful as an activity-specific or predictive biomarker in systemic lupus erythematosus (SLE). METHODS: Serum TNC levels were determined by enzyme-linked immunosorbent assay at inception visit in a prospective cohort of 59 SLE patients, and in 65 healthy controls (HC). SLE patients were followed for a mean of 11 months, disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) and British Isles Lupus Assessment Group disease activity index (BILAG-2004), clinical and laboratory data were recorded every 3-6 months, and changes in glucocorticoids (GC) and immunosuppressants (IS) were recorded serially. We examined cross-sectionally the relationships between serum concentrations of TNC and SLE status, SLEDAI-2 K scores, strata of disease activity, and levels of conventional biomarkers [anti-double-stranded DNA (dsDNA), anti-nucleosome antibodies, C3 and C4]. We also explored the utility of TNC levels for predicting disease flares, defined as (i) new/increased GC, (ii) new/increased GC or IS, and (iii) increase in SLEDAI by ≥3 or (iv) BILAG A or B flare. RESULTS: There was no significant difference in the mean levels of TNC between the SLE patients and HC. However, in SLE patients with active disease (SLEDAI ≥6), the TNC levels were significantly higher than in the HC (p = 0.004) or in patients with no/low disease activity (p = 0.004). In SLE patients, TNC levels were significantly associated with positivity of anti-dsDNA (p = 0.03) and anti-nucleosome antibodies (p = 0.008). Flares defined by a need to escalate immunosuppressive therapy were captured more frequently and earlier than flares defined by standard activity indices. Higher baseline levels of serum TNC presented a significantly greater risk of flare (i) [hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.11-1.73] or (ii) (HR 1.25, 95% CI 1.02-1.52) but not of flares (iii) or (iv). The baseline serum TNC level was the single most important independent predictor of flare (i) compared with conventional biomarkers. CONCLUSIONS: TNC is not disease-specific, but it seems to indicate the activity of SLE and may predict the need to escalate immunosuppressive therapy. TNC levels may thus serve as a useful activity-specific and predictive biomarker in SLE.

Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic

Institute of Rheumatology Prague and Department of Rheumatology 1st Faculty of Medicine Charles University Prague Na Slupi 4 Praha 2 12850 Prague Czech Republic

Zobrazit více v PubMed

Illei GG, Tackey E, Lapteva L, Lipsky PE. Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum. 2004;50:2048–65. doi: 10.1002/art.20345. PubMed DOI

Liu CC, Manzi S, Ahearn JM. Biomarkers for systemic lupus erythematosus: a review and perspective. Curr Opin Rheumatol. 2005;17:543–9. doi: 10.1097/01.bor.0000174182.70159.22. PubMed DOI

Esdaile JM, Abrahamowicz M, Joseph L, MacKenzie T, Li Y, Danoff D. Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus: why some tests fail. Arthritis Rheum. 1996;39:370–8. doi: 10.1002/art.1780390304. PubMed DOI

Midwood KS, Hussenet T, Langlois B, Orend G. Advances in tenascin-C biology. Cell Mol Life Sci. 2011;68:3175–99. doi: 10.1007/s00018-011-0783-6. PubMed DOI PMC

Midwood KS, Orend G. The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal. 2009;3:287–310. doi: 10.1007/s12079-009-0075-1. PubMed DOI PMC

Chiquet-Ehrismann R, Chiquet M. Tenascins: regulation and putative functions during pathological stress. J Pathol. 2003;200:488–99. doi: 10.1002/path.1415. PubMed DOI

Udalova IA, Ruhmann M, Thomson SJ, Midwood KS. Expression and immune function of tenascin-C. Crit Rev Immunol. 2011;31:115–45. doi: 10.1615/CritRevImmunol.v31.i2.30. PubMed DOI

Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med. 2009;15:774–80. doi: 10.1038/nm.1987. PubMed DOI

Goh FG, Piccinini AM, Krausgruber T, Udalova IA, Midwood KS. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol. 2010;184:2655–62. doi: 10.4049/jimmunol.0903359. PubMed DOI

Ruhmann M, Piccinini AM, Kong PL, Midwood KS. Endogenous activation of adaptive immunity: tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease. Arthritis Rheum. 2012;64:2179–90. doi: 10.1002/art.34401. PubMed DOI

Sumioka T, Fujita N, Kitano A, Okada Y, Saika S. Impaired angiogenic response in the cornea of mice lacking tenascin C. Invest Ophthalmol Vis Sci. 2011;52:2462–7. doi: 10.1167/iovs.10-5750. PubMed DOI

Hisatomi K, Sakamoto N, Mukae H, Hayashi T, Amenomori M, Ishimoto H, et al. Elevated levels of tenascin-C in patients with cryptogenic organizing pneumonia. Intern Med. 2009;48:1501–7. doi: 10.2169/internalmedicine.48.2233. PubMed DOI

Tanaka H, El-Karef A, Kaito M, Kinoshita N, Fujita N, Horiike S, et al. Circulating level of large splice variants of tenascin-C is a marker of piecemeal necrosis activity in patients with chronic hepatitis C. Liver Int. 2006;26:311–8. doi: 10.1111/j.1478-3231.2005.01229.x. PubMed DOI

Riedl S, Tandara A, Reinshagen M, Hinz U, Faissner A, Bodenmüller H, et al. Serum tenascin-C is an indicator of inflammatory bowel disease activity. Int J Colorectal Dis. 2001;16:285–91. doi: 10.1007/s003840100312. PubMed DOI

Imanaka-Yoshida K, Hiroe M, Yasutomi Y, Toyozaki T, Tsuchiya T, Noda N, et al. Tenascin-C is a useful marker for disease activity in myocarditis. J Pathol. 2002;197:388–94. doi: 10.1002/path.1131. PubMed DOI

Wallner K, Li C, Shah PK, Fishbein MC, Forrester JS, Kaul S, et al. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation. 1999;99:1284–9. doi: 10.1161/01.CIR.99.10.1284. PubMed DOI

Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Rotellar F, Valentí V, et al. Increased tenascin C and Toll-like receptor 4 levels in visceral adipose tissue as a link between inflammation and extracellular matrix remodeling in obesity. J Clin Endocrinol Metab. 2012;97:E1880–9. doi: 10.1210/jc.2012-1670. PubMed DOI PMC

Page TH, Charles PJ, Piccinini AM, Nicolaidou V, Taylor PC, Midwood KS. Raised circulating tenascin-C in rheumatoid arthritis. Arthritis Res Ther. 2012;14:R260. doi: 10.1186/ar4105. PubMed DOI PMC

Shukla A, Gaur P, Aggarwal A. Tenascin-C levels, a Toll-like receptor 4 ligand, in enthesitis-related arthritis category of juvenile idiopathic arthritis: a cross-sectional and longitudinal study. J Rheumatol. 2015;42:891–6. doi: 10.3899/jrheum.141365. PubMed DOI

Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. doi: 10.1002/art.1780400928. PubMed DOI

Gladman DD, Ibanez D, Urowitz MB. Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol. 2002;29:288–91. PubMed

Isenberg DA, Rahman A, Allen E, Farewell V, Akil M, Bruce IN, et al. BILAG 2004: development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005;44:902–6. doi: 10.1093/rheumatology/keh624. PubMed DOI

Abrahamowicz M, Fortin PR, du Berger R, Nayak V, Neville C, Liang MH. 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. 1998;25:277–84. PubMed

Inoue K, Jinnin M, Hara Y, Makino K, Kajihara I, Makino T, et al. Serum levels of tenascin-C in collagen diseases. J Dermatol. 2013;40:715–9. doi: 10.1111/1346-8138.12218. PubMed DOI

Truong LD, Pindur J, Barrios R, D’Agati V, Lechago J, Suki W, et al. Tenascin is an important component of the glomerular extracellular matrix in normal and pathologic conditions. Kidney Int. 1994;45:201–10. doi: 10.1038/ki.1994.24. PubMed DOI

Brissett M, Veraldi KL, Pilewski JM, Medsger TA, Jr, Feghali-Bostwick CA. Localized expression of tenascin in systemic sclerosis-associated pulmonary fibrosis and its regulation by insulin-like growth factor binding protein 3. Arthritis Rheum. 2012;64:272–80. doi: 10.1002/art.30647. PubMed DOI PMC

Imanaka-Yoshida K. Tenascin-C in cardiovascular tissue remodeling: from development to inflammation and repair. Circ J. 2012;76:2513–20. doi: 10.1253/circj.CJ-12-1033. PubMed DOI

Jakovcevski I, Miljkovic D, Schachner M, Andjus PR. Tenascins and inflammation in disorders of the nervous system. Amino Acids. 2013;44:1115–27. doi: 10.1007/s00726-012-1446-0. PubMed DOI

Jyo Y, Sasaki T, Nomura S, Tamai H, Kawai S, Osawa G, et al. Expression of tenascin in mesangial injury in experimental glomerulonephritis. Exp Nephrol. 1997;5:423–8. PubMed

Masaki T, Yorioka N, Taniguchi Y, Oda H, Yamakido M. Tenascin expression may reflect the activity and chronicity of human IgA nephropathy. Clin Nephrol. 1998;50:205–13. PubMed

Hörstrup JH, Gehrmann M, Schneider B, Plöger A, Froese P, Schirop T, et al. Elevation of serum and urine levels of TIMP-1 and tenascin in patients with renal disease. Nephrol Dial Transplant. 2002;17:1005–13. doi: 10.1093/ndt/17.6.1005. PubMed DOI

Liang MH, Simard JF, Costenbader K, Dore BT, Ward M, Fortin PR, et al. Methodologic issues in the validation of putative biomarkers and surrogate endpoints in treatment evaluation for systemic lupus erythematosus. Endocr Metab Immune Disord Drug Targets. 2009;9:108–12. doi: 10.2174/187153009787582388. PubMed DOI PMC

Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. Lupus. 1999;8:685–91. doi: 10.1191/096120399680411281. PubMed DOI

Yee CS, Farewell VT, Isenberg DA, Griffiths B, Teh LS, Bruce IN, et al. The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients. Rheumatology (Oxford) 2011;50:982–8. doi: 10.1093/rheumatology/keq376. PubMed DOI PMC

American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: measures of overall disease activity. Arthritis Rheum. 2004;50:3418–26. doi: 10.1002/art.20628. PubMed DOI

Yee CS, Isenberg DA, Prabu A, Sokoll K, Teh LS, Rahman A, et al. BILAG-2004 index captures systemic lupus erythematosus disease activity better than SLEDAI-2000. Ann Rheum Dis. 2008;67:873–6. doi: 10.1136/ard.2007.070847. PubMed DOI

Li T, Prokopec SD, Morrison S, Lou W, Reich H, Gladman D, et al. Anti-nucleosome antibodies outperform traditional biomarkers as longitudinal indicators of disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 2015;54:449–57. doi: 10.1093/rheumatology/keu326. PubMed DOI PMC

Cella N, Chiquet-Ehrismann R, Hynes NE. Lactogenic hormones and tenascin-C regulate C/EBPα and β in mammary epithelial cells. J Cell Biochem. 2000;76:394–403. doi: 10.1002/(SICI)1097-4644(20000301)76:3<394::AID-JCB7>3.0.CO;2-B. PubMed DOI

Elevated Tenascin-C Serum Levels in Patients With Axial Spondyloarthritis