Skip to main content

Advertisement

SpringerLink
Log in

Use of Biomarkers in the Management of Children with Lupus

  • PEDIATRIC RHEUMATOLOGY (TJA LEHMAN, SECTION EDITOR)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Childhood systemic lupus erythematosus (SLE) is known to have a worse prognosis than adult-onset disease, and monitoring and treatment of the disease are still a challenge. Thus, there is an urgent need for highly reliable, non-invasive biomarkers for early detection of relapses, to avoid long-term complications and to optimize the management of children with LN. Recent studies of pediatric patients have yielded novel specific biomarkers for SLE diagnosis which can be used for monitoring disease activity and response to treatment. The most promising biomarkers in juvenile-onset SLE include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and alpha-1-acid glycoprotein. None of these might be suitable for use as a single SLE-biomarker. More likely a combination of novel biomarkers with traditionally used data, including autoantibodies and complement, might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of relapses.cp

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Midgley A, Beresford MW. Cellular localization of nuclear antigen during neutrophil apoptosis: mechanisms for autoantigen exposure? Lupus. 2011;20(6):641–6.

    Article  PubMed  CAS  Google Scholar 

  2. Pan Y, Sawalha AH. Epigenetic regulation and the pathogenesis of systemic lupus erythematodes. Transl Res. 2009;153(1):4–10.

    Article  PubMed  CAS  Google Scholar 

  3. Ahearn JM, Liu CC, Kao AH, et al. Biomarkers for systemic lupus erythematosus. Transl Res. 2012;159:326–42.

    Article  PubMed  CAS  Google Scholar 

  4. Cook HT, Botto M. Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythematodes. Nat Clin Prac Rheumatol. 2006;2(6):330–7.

    Article  CAS  Google Scholar 

  5. Watson L, Beresford MW. Urine biomarkers in juvenile-onset SLE nephritis. Published online Pediatr Nephrol. 2012; doi:10.1007/s00467-012-2184-y

  6. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.

    Article  PubMed  CAS  Google Scholar 

  7. Hersh AO, Trupin L, Yazdany J, et al. Childhood-onset disease as a predictor of mortality in an adult cohort of patients with systemic lupus erythematodes. Arthritis Care Res. 2012;62(8):1152–9.

    Article  Google Scholar 

  8. Liu CC, Ahearn JM. The search for lupus biomarkers. Best Pract Res Clin Rheumatol. 2009;23:507–23.

    Article  PubMed  CAS  Google Scholar 

  9. Liang MH, Socher SA, Larson MG, et al. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythemotodes. Arthritis Rheum. 1989;32(9):1107–18.

    Article  PubMed  CAS  Google Scholar 

  10. Faurschou M, Starklint H, Halberg P, et al. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol. 2006;33(8):1563–9.

    PubMed  Google Scholar 

  11. Chun HY, Chung JW, Kim HA, et al. Cytokine IL6 and IL10 as biomarkers in systemic lupus erythematosus. J Clin Immunol. 2007;27:461–6.

    Article  PubMed  CAS  Google Scholar 

  12. Illei GG, Tackey E, Lapteva L, et al. Biomarkers in systemic lupus erythematosus. I. General overview of biomarkers and their applicability. Arthritis Rheum. 2004;50(6):1709–20.

    Article  PubMed  CAS  Google Scholar 

  13. Rahman A, Isenberg DA. Systemic lupus erythematodes. N Engl J Med. 2008;358(9):929–39.

    Article  PubMed  CAS  Google Scholar 

  14. Ching KH, Burbelo PD, Tipton C, et al. Two major autoantibody clusters in systemic lupus erythematosus. Plosone. 2012;7(2):1–11.

    Google Scholar 

  15. Jurencak R, Fritzler M, Tyrrell P, et al. Autoantibodies in pediatric systemic lupus erythematosus: ethic grouping, cluster analysis, and clinical correlations. J Rheumatol. 2009;36:416–21.

    Article  PubMed  Google Scholar 

  16. Simon JA, Cabiedes J, Ortiz E, et al. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology. 2004;43:220–4.

    Article  PubMed  CAS  Google Scholar 

  17. Malleson PN, Sailer M, Mackinnon MJ. Usefulness of antinuclear antibody testing to screen for rheumatic disease. Arch Dis Child. 1997;77:299–304.

    Article  PubMed  CAS  Google Scholar 

  18. McGhee JL, Kickingbird LM, Jarvis JN. Clinical utility of antinuclear antibody tests in children. BMC Pediatr. 2004;4:13.

    Article  PubMed  Google Scholar 

  19. Jesus AA, Silva CA, Carneiro-Sampaio M, et al. Anti-C1q antibodies in juvenile-onset systemic lupus erythematodes. Ann N Y Acad Sci. 2009;1173:235–8.

    Article  PubMed  CAS  Google Scholar 

  20. Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;638413:1–13.

    Article  Google Scholar 

  21. • Liu CC, Manzi S, Kao AH, et al. Cell-bound complement biomarkers for SLE: from benchtop to bedside. Rheum Dis Clin North Am. 2010;36(1):161–72. Liu et al. summarized studies performed on different cell-bound complement activation proteins. Significant results showed that those cell-bound complement components may perform more reliably than soluble complements proteins as biomarkers for SLE.

    Article  PubMed  CAS  Google Scholar 

  22. Porcel JM, Ordo J, Castro-Salomo A, et al. The value of complement activation products in the assessment of systemic lupus erythematosus flares. Clin Immunol Immunopathol. 1995;74:2883–8.

    Article  Google Scholar 

  23. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematodes. Medicine (Baltimore). 2006;85(3):147–56.

    Article  Google Scholar 

  24. Welch TR, Blystone LW. Renal disease associated with inherited disorders of the complement system. Pediatr Nephrol. 2009;24(8):149–1444.

    Article  Google Scholar 

  25. Manzi S, Navratil JS, Ruffing MJ. Measurements of erythrocyte C4d and complement receptor 1 in the diagnosis of systemic lupus erythematodes. Arthritis Rheum. 2004;50(11):3596–604.

    Article  PubMed  CAS  Google Scholar 

  26. Navratil JS, Manzi S, Kao AH. Platlet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):670–4.

    Article  PubMed  CAS  Google Scholar 

  27. Liu CC, Kao AH, Hawkins DM, et al. Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus. Clin Transl Sci. 2009;2(4):300–8.

    Article  PubMed  CAS  Google Scholar 

  28. Yang DH, Chang DM, Lai JH, et al. Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus. Rheumatology. 2009;48:1083–7.

    Article  PubMed  CAS  Google Scholar 

  29. Arce E, Jacksan DG, Gill MA, et al. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic Lupus Erythematosus. J Immunol. 2001;167:2361–9.

    PubMed  CAS  Google Scholar 

  30. Folzenlogen D, Hofer MF, Leung DY, et al. Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients. Clin Immunol Immunopathol. 1997;83:199–204.

    Article  PubMed  CAS  Google Scholar 

  31. Jacobi AM, Reiter K, Mackay M, et al. Activated Memory B Cell Subsets Correlate With Disease Activity in Systemic Lupus Erythematosus. Delineation by Expression of CD27, IgD, and CD95. Arthritis & Rheumatology 2008; 58(6):1762–1773

    Google Scholar 

  32. Bijl M, Horst G, Limburg PC, et al. Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus. Ann Rheum Dis. 2001;60:523–6.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10.

    PubMed  CAS  Google Scholar 

  34. Villard JF, Bloch-Michel C, Neau-Cransac M, et al. HLA-DR expression on lymphocyte subsets as a marker of disease activity in patients with systemic lupus erythematosus. Clin Exp Immunol. 2001;125:485–91.

    Article  Google Scholar 

  35. Dai Z, Turtle CJ, Booth GC, et al. Normally occurring NKG2D+ CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile onset lupus. J Exp Med. 2009;206(4):793–805.

    Article  PubMed  CAS  Google Scholar 

  36. Nath SK, Kilpatrick J, Harley JB. Genetics of human systemic lupus erythematodes: the emerging picture. Curr Opin Immunol. 2004;16(6):794–800.

    Article  PubMed  CAS  Google Scholar 

  37. Sestak AL, Nath SK, Sawalha AH. Current status of lupus genetics. Arthritis Res Ther. 2007;9(3):2010.

    Article  Google Scholar 

  38. Yang Y, Chang EK, Zhou B. The intricate role of complement component C4 in human systemic lupus erythematodes. Curr Dir Autoimmun. 2004;7:98–113.

    Article  PubMed  CAS  Google Scholar 

  39. Al-Mayouf SM, Abanomi H, Eldali A. Impact of C1q deficiency on the severity and outcome of childhood systemic lupus erythematosus. Int J Rheum Dis. 2011;14(1):81–5.

    Article  PubMed  Google Scholar 

  40. Nikpour M, Dempsey AA, Urowitz MB, et al. Association of a gene expression profile from whole blood with disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2008;67:1069–75.

    Article  PubMed  CAS  Google Scholar 

  41. Kozyrev SV, Alarcon-Riquelme ME. The genetics and biology of Irf5-mediated signalling in lupus. Autoimmunity. 2007;40(8):591–601.

    Article  PubMed  CAS  Google Scholar 

  42. Kyogoku C, Langefeld CD, Ortmann WA. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PtPn22 with human SLE. Am J Hum Genet. 2004;75(3):504–7.

    Article  PubMed  CAS  Google Scholar 

  43. Firestein GS. Kelley’s textbook of rheumatology. Philadelphia: Elsevier WB Saunders; 2008. p. 1270.

    Google Scholar 

  44. Marini R, Costallat LT. Young age at onset, renal involvement, and arterial hypertension are of adverse prognostic significance in juvenile systemic lupus erythematodes. Rev Rheum Engl Ed. 1999;6(6):303–9.

    Google Scholar 

  45. Zabaleta-Lanz ME, Munoz LE, Tapanes FJ, et al. Further description of early clinically silent lupus nephritis. Lupus. 2006;15(12):845–51.

    Article  PubMed  CAS  Google Scholar 

  46. Mak A, Mok CC, Chu WP, et al. Renal damage in systemic lupus erythematodes: a comparative analysis of different age groups. Lupus. 2007;16(1):28–34.

    Article  PubMed  CAS  Google Scholar 

  47. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erithematous revisited. J Am Soc Nephrol. 2004;15:241–50.

    Article  PubMed  Google Scholar 

  48. Hiraki LT, Lu B, Alexander SR, et al. Endstage renal disease due to lupus nephritis among children in the US, 1995–2006. Arthritis Rheum. 2011;63(7):1988–97.

    Article  PubMed  Google Scholar 

  49. Watson L, Midgley A, Pilkington C, et al. Urinary monocyte chemoattractant protein 1 and alpha 1 acid glycoprotein as biomarkers of renal disease activity in juvenile-onset systemic lupus erythematosus. Lupus. 2012;21:496–501.

    Article  PubMed  CAS  Google Scholar 

  50. Fine DM, Ziegenbein M, Petri M, et al. A prospective study of protein excretion using short-interval timed urine collections in patients with lupus nephritis. Kidney Int. 2009;76(12):1284–8.

    Article  PubMed  CAS  Google Scholar 

  51. Ayodele OE, Okpechi IG, Swanepoel CR. Predictors of poor renal outcome in patients with biopsy-proven lupus nephritis. Nephrology. 2010;15(4):482–90.

    Article  PubMed  Google Scholar 

  52. Schwartz N, Michaelson JS, Putterman C. Lipocalin-2, TWEAK, and other cytokines as urinary biomarkers for lupus nephritis. Ann N Y Acad Sci. 2007;1109:265–74.

    Article  PubMed  CAS  Google Scholar 

  53. Gwira JA, Wei F, Ishibe S, et al. Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem. 2005;280(9):7875–82.

    Article  PubMed  CAS  Google Scholar 

  54. Brunner HI, Mueller M, Rutherford C, et al. Urinary neutrophil gelatinase–associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol. 2006;54(8):2577–84.

    Article  CAS  Google Scholar 

  55. Hinze CH, Suzuki M, Klein-Gitelman M, et al. Neutrophil Gelatinase-associated Lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Arthritis Rheum. 2009;60:2772–81.

    Article  PubMed  Google Scholar 

  56. • Brunner HI, Bennett MR, Mina R, et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheumatol. 2012;64(8):2687–97. Brunner et al. investigated urine samples of 76 patients for novel urinary biomarkers, established markers of renal function, and compared these with histologic features of LN. Different increases in levels of specific biomarkers reflecting histological features seen in either active or chronic LN could be observed. This study showed that a combination of urinary markers together with established markers could serve as a biomarker panel.

    Article  CAS  Google Scholar 

  57. Rovin BH, Birmingham DJ, Nagaraja HN, et al. Biomarker discovery in human SLE nephritis. Bulletin of the NYU Hospital of Joint Diseases. 2007;65(3):187–93.

    Google Scholar 

  58. Rubinstein T, Pitashny M, Levine B, et al. Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. Rheumatology. 2010;49(5):960–71.

    Article  PubMed  CAS  Google Scholar 

  59. Hinze CH, Suzuki M, Klein-Gitelman M, et al. Neutrophil Gelatinase-associated Lipocalin anticipates the Course of Global and Renal Childhood-Onset Systemic Lupus Erythematosus Disease Activity. Arthritis Rheum. 2009;60(9):2772–81.

    Article  PubMed  Google Scholar 

  60. Marks SD, Williams SJ, Tullus K, et al. Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. Nephrol Dial Transpl. 2008;23:3521–6.

    Article  CAS  Google Scholar 

  61. Marks SD, Shah V, Pilkington C, et al. Urinary monocyte chemoattractant protein-1 correlates with disease activity in lupus nephritis. Pediatr Nephrol. 2012;25:2283–22889.

    Article  Google Scholar 

  62. Hammad AM, Youssef HM, El-Arman MM. Transforming growth factor beta 1 in children with systemic lupus erythematosus: a possible relation with clinical presentation of lupus nephritis. Lupus. 2006;15:608–12.

    Article  PubMed  CAS  Google Scholar 

  63. Marks SD, Shah V, Pilkington C, et al. Renal tubular dysfunction in children with systemic lupus erythematosus. Pediatr Nephrol. 2005;20:141–8.

    Article  PubMed  Google Scholar 

  64. Suzuki M, Wiers K, Brooks EB, et al. Initial validation of a novel biomarker panel for active pediatric lupus nephritis. Pediatr Res. 2009;65:530–6.

    Article  PubMed  CAS  Google Scholar 

  65. Suzuki M, Ross GF, Wiers K, et al. Identification of urinary proteomics signature for lupus nephritis in children. Pediatr Nephrol. 2007;22:2047–57.

    Article  PubMed  Google Scholar 

  66. Chaussabel D, Quinn C, Shen J, et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity. 2008;29(1):150–64.

    Article  PubMed  CAS  Google Scholar 

  67. Brunner HI, Huggins J, Klein-Gitelman MS. Pediatric SLE – towards a comprehensive management plan. Nat Rev Rheumatol. 2011;7(4):225–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Pediatrics 1, Medical University Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria

    Elisabeth Binder & Monika Edelbauer

Authors
  1. Elisabeth Binder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika Edelbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Edelbauer.

Additional information

This article is part of the Topical Collection on Pediatric Rheumatology

Rights and permissions

Reprints and permissions

About this article

Cite this article

Binder, E., Edelbauer, M. Use of Biomarkers in the Management of Children with Lupus. Curr Rheumatol Rep 15, 312 (2013). https://doi.org/10.1007/s11926-012-0312-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-012-0312-0

Keywords

Search

Navigation