Skip to main content

Advertisement

Log in

Biomarkers for Childhood-Onset Systemic Lupus Erythematosus

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Childhood-onset systemic lupus erythematosus (cSLE) is a systemic autoimmune disease characterized by the presence of autoantibodies. cSLE often affects multiple organs in the body and is known to have a poorer prognosis than adult-onset disease (Azevedo et al. 2014). Current laboratory tests are clearly insufficient for identifying and monitoring the disease. Recent studies have yielded novel biomarkers for cSLE which can be used for monitoring disease activity and response to treatment. The most encouraging biomarkers will be discussed herein and include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and others. Previous studies suggested that a combination of the novel biomarkers might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of cSLE flares.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

  1. Azevedo PC, Murphy G, Isenberg DA. Pathology of systemic lupus erythematosus: the challenges ahead. Systemic Lupus Erythematosus: Springer; 2014. p. 1–16. This a good up-to-date article about the pathogenesis of SLE.

  2. Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset before adulthood. Arthritis Care Res. 2012;64(12):1787–93.

    Article  Google Scholar 

  3. Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

    Article  Google Scholar 

  4. Ziegler A, König I, Schulz-Knappe M. Challenges in planning and conducting diagnostic studies with molecular biomarkers. Dtsch Med Wochenschr. 2013;138(19):2–24. This is an article that talks about the challenges in biomarker research.

    Article  Google Scholar 

  5. Devarajan P. Proteomics for biomarker discovery in acute kidney injury. Semin Nephrol. 2007;27(6):637–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Knepper MA. Proteomics and the kidney. J Am Soc Nephrol: JASN. 2002;13(5):1398–408.

    Article  CAS  PubMed  Google Scholar 

  7. Bennett MR, Devarajan P. Proteomic analysis of acute kidney injury: biomarkers to mechanisms. PROTEOMICS-Clin Appl. 2011;5(1–2):67–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Knepper MA. Common sense approaches to urinary biomarker study design. J Am Soc Nephrol: JASN. 2009;20(6):1175–8.

    Article  PubMed  Google Scholar 

  9. Costenbader KH, Desai A, Alarcon GS, Hiraki LT, Shaykevich T, Brookhart MA, et al. Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006. Arthritis Rheum. 2011;63(6):1681–8.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Hiraki LT, Lu B, Alexander SR, Shaykevich T, Alarcon GS, Solomon DH, et al. End-stage renal disease due to lupus nephritis among children in the US, 1995–2006. Arthritis Rheum. 2011;63(7):1988–97.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res. 2012;64(6):797–808.

    Article  Google Scholar 

  12. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–50.

    Article  PubMed  Google Scholar 

  13. Reich HN, Landolt-Marticorena C, Boutros PC, John R, Wither J, Fortin PR, et al. Molecular markers of injury in kidney biopsy specimens of patients with lupus nephritis. J Mol Diagn. 2011;13(2):143–51.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Rovin BH. The chemokine network in systemic lupus erythematous nephritis. Front Biosci: J Virtual Libr. 2008;13:904–22.

    Article  CAS  Google Scholar 

  15. Kiani AN, Johnson K, Chen C, Diehl E, Hu H, Vasudevan G, et al. Urine osteoprotegerin and monocyte chemoattractant protein-1 in lupus nephritis. J Rheumatol. 2009;36(10):2224–30.

    Article  CAS  PubMed  Google Scholar 

  16. Rovin BH, Song H, Birmingham DJ, Hebert LA, Yu CY, Nagaraja HN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol: JASN. 2005;16(2):467–73.

    Article  CAS  PubMed  Google Scholar 

  17. Tucci M, Barnes EV, Sobel ES, Croker BP, Segal MS, Reeves WH, et al. Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis. Arthritis Rheum. 2004;50(6):1842–9.

    Article  CAS  PubMed  Google Scholar 

  18. Watson L, Midgley A, Pilkington C, Tullus K, Marks S, Holt R, 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(5):496–501. This article shows the importance of urine MCP1 and AGP as biomarkers.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Jin M, Wu H, Nadasdy T, Nadasdy G, Harris N, et al. Biomarkers of lupus nephritis determined by serial urine proteomics. Kidney Int. 2008;74(6):799–807.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Bacchetta J, Cochat P, Rognant N, Ranchin B, Hadj-Aissa A, Dubourg L. Which creatinine and cystatin C equations can be reliably used in children? Clin J Am Soc Nephrol: CJASN. 2011;6(3):552–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Pitashny M, Schwartz N, Qing X, Hojaili B, Aranow C, Mackay M, et al. Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum. 2007;56(6):1894–903.

    Article  CAS  PubMed  Google Scholar 

  23. Menke J, Iwata Y, Rabacal WA, Basu R, Yeung YG, Humphreys BD, et al. CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest. 2009;119(8):2330–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Torres-Salido MT, Cortes-Hernandez J, Vidal X, Pedrosa A, Vilardell-Tarres M, Ordi-Ros J. Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014.

  25. Suzuki M, Wiers KM, Klein-Gitelman MS, Haines KA, Olson J, Onel KB, et al. Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis. Pediatr Nephrol. 2008;23(3):403–12.

    Article  PubMed  Google Scholar 

  26. Hinze CH, Suzuki M, Klein-Gitelman M, Passo MH, Olson J, Singer NG, 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(9):2772–81.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, et al. Identification of a urinary proteomic signature for lupus nephritis in children. Pediatr Nephrol. 2007;22(12):2047–57.

    Article  PubMed  Google Scholar 

  28. Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 2004;14(11):628–38.

    Article  CAS  PubMed  Google Scholar 

  29. Menke J, Amann K, Cavagna L, Blettner M, Weinmann A, Schwarting A, et al. Colony stimulating factor 1: a potential biomarker for lupus nephritis. Journal of the American Society of Nephrology: JASN. 2014. This article introduces a new biomarker.

  30. Wang G, Tam LS, Li EK, Kwan BC, Chow KM, Luk CC, et al. Serum and urinary free microRNA level in patients with systemic lupus erythematosus. Lupus. 2011;20(5):493–500.

    Article  CAS  PubMed  Google Scholar 

  31. Rönnblom L, Eloranta M-L. The interferon signature in autoimmune diseases. Curr Opin Rheumatol. 2013;25(2):248–53. This is a good review regarding IFN role in autoimmune diseases.

    Article  PubMed  Google Scholar 

  32. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6):711–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Landolt-Marticorena C, Bonventi G, Lubovich A, Ferguson C, Unnithan T, Su J, et al. Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2009;68(9):1440–6.

    Article  CAS  PubMed  Google Scholar 

  34. Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum. 2009;60(10):3098–107.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Skeoch S, Haque S, Pemberton P, Bruce I. Cell adhesion molecules as potential biomarkers of nephritis, damage and accelerated atherosclerosis in patients with SLE. Lupus. 2014. This article introduces cell adhesion molecules as potential biomarkers.

  36. Batal I, Liang K, Bastacky S, Kiss L, McHale T, Wilson N, et al. Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study. Lupus. 2011;0961203311422093.

  37. Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum. 2012;64(8):2687–97. This article talks about biomarkers in relation with histology.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Dall’Era M, Stone D, Levesque V, Cisternas M, Wofsy D. Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide. Arthritis Care Res. 2011;63(3):351–7.

    Google Scholar 

  39. Hanly JG, Fisk JD, McCurdy G, Fougere L, Douglas JA. Neuropsychiatric syndromes in patients with systemic lupus erythematosus and rheumatoid arthritis. J Rheumatol. 2005;32(8):1459–6.

    PubMed  Google Scholar 

  40. Kozora E, West SG, Maier SF, Filley CM, Arciniegas DB, Brown M, et al. Antibodies against N-methyl-D-aspartate receptors in patients with systemic lupus erythematosus without major neuropsychiatric syndromes. J Neurol Sci. 2010;295(1–2):87–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001;7(11):1189–93.

    Article  CAS  PubMed  Google Scholar 

  42. Hanly JG, Robichaud J, Fisk JD. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol. 2006;33(8):1553–8.

    CAS  PubMed  Google Scholar 

  43. Sato S, Kawashima H, Hoshika A, Yoshio T. Clinical analysis of anti-NR2 glutamate receptor antibodies and interleukin-6 with neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford). 2011;50(11):2142–4.

    Article  CAS  Google Scholar 

  44. Weissman JD, Khunteev GA, Heath R, Dambinova SA. NR2 antibodies: risk assessment of transient ischemic attack (TIA)/stroke in patients with history of isolated and multiple cerebrovascular events. J Neurol Sci. 2011;300(1–2):97–102.

    Article  CAS  PubMed  Google Scholar 

  45. Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Clarke A, et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis. 2011;70(10):1726–32.

    Article  CAS  PubMed  Google Scholar 

  46. Mostafa GA, Ibrahim DH, Shehab AA, Mohammed AK. The role of measurement of serum autoantibodies in prediction of pediatric neuropsychiatric systemic lupus erythematosus. J Neuroimmunol. 2010;227(1–2):195–201.

    Article  CAS  PubMed  Google Scholar 

  47. Appenzeller S, Amorim BJ, Ramos CD, Rio PA, de Etchebehere EC, Camargo EE, et al. Voxel-based morphometry of brain SPECT can detect the presence of active central nervous system involvement in systemic lupus erythematosus. Rheumatology (Oxford). 2007;46(3):467–72.

    Article  CAS  Google Scholar 

  48. Appenzeller S, Bonilha L, Rio PA, Min Li L, Costallat LT, Cendes F. Longitudinal analysis of gray and white matter loss in patients with systemic lupus erythematosus. Neuroimage. 2007;34(2):694–701.

    Article  PubMed  Google Scholar 

  49. Bosma GP, Steens SC, Petropoulos H, Admiraal-Behloul F, van den Haak A, Doornbos J, et al. Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2004;50(10):3195–202.

    Article  PubMed  Google Scholar 

  50. DiFrancesco MW, Gitelman DR, Klein-Gitelman MS, Sagcal-Gironella ACP, Zelko F, Beebe D, et al. Functional neuronal network activity differs with cognitive dysfunction in childhood-onset systemic lupus erythematosus. Arthritis Res Ther. 2013;15(R40):available online as Provisional PDF.

  51. Brunner H, Klein-Gitelman M. Lupus in the child’s mind.

  52. Klein-Gitelman M, Cedeno A, Baker A, Zelko F, Beebe D, Dina B, et al. Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit. Arthritis Rheum-Us. 2011;63(10):S293. This article talks about imaging as a biomarker in lupus.

    Google Scholar 

  53. Pilz S, Horejsi R, Moller R, Almer G, Scharnagl H, Stojakovic T, et al. Early atherosclerosis in obese juveniles is associated with low serum levels of adiponectin. J Clin Endocrinol Metab. 2005;90(8):4792–6.

    Article  CAS  PubMed  Google Scholar 

  54. Zoccali C, Mallamaci F, Panuccio V, Tripepi G, Cutrupi S, Parlongo S, et al. Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors. Kidney Int Suppl. 2003;84:S98–102.

    Article  CAS  PubMed  Google Scholar 

  55. Al M, Ng L, Tyrrell P, Bargman J, Bradley T, Silverman E. Adipokines as novel biomarkers in paediatric systemic lupus erythematosus. Rheumatology. 2009:kep030.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Khalid M Abulaban and Hermine I. Brunner declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hermine I. Brunner.

Additional information

This article is part of the Topical Collection on Pediatric Rheumatology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abulaban, K.M., Brunner, H.I. Biomarkers for Childhood-Onset Systemic Lupus Erythematosus. Curr Rheumatol Rep 17, 471 (2015). https://doi.org/10.1007/s11926-014-0471-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-014-0471-2

Keywords

Navigation