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Journal of Neurology

, Volume 261, Issue 9, pp 1706–1714 | Cite as

Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: a systematic review

  • Savino Sciascia
  • Maria Laura Bertolaccini
  • Dario Roccatello
  • Munther A. Khamashta
  • Giovanni SannaEmail author
Original Communication

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most important manifestations of SLE, and includes a variety of clinical manifestations, classified by the American College of Rheumatology in 19 different neuropsychiatric syndromes. To date, more than 116 antibodies have been reported in SLE and at least 20 of them, including 11 brain-specific and 9 systemic antibodies, have been controversially associated with NPSLE. To systematically review the available evidence, to define the association between the above antibodies and NPSLE as a whole and with the 19 neuropsychiatric syndromes associated with SLE, by strictly applying the American College Rheumatology case definitions. Medline reports published between 1999 and 2013 investigating the association between antibodies and NPSLE were included. Whenever possible, associations between antibodies and both NPSLE as a whole and with the 19 syndromes were analysed. This systematic review is based on available data from more than 8,000 patients and controls from 42 studies analysing antibodies and NPSLE. Nineteen studies analysed the role of antiphospholipid antibodies (aPL), 11 focused on anti-ribosomal-P protein antibodies and 5 on anti-N-Methyl-d-Aspartate receptor antibodies. Two studies analysed, respectively, antibodies to aquaporin-4 and VH4-34 encoded antibodies. Given the multitude of clinical manifestations related to NPSLE, a single biomarker failed to be reliably associated with all neuropsychiatric events. Our findings provide evidence that aPL, mainly the lupus anticoagulant, and anti-ribosomal P antibodies are significantly associated with specific manifestations of neuropsychiatric disease attributed to SLE, namely, cerebrovascular events and psychosis, respectively.

Keywords

Systemic lupus erythematosus Stroke Antiphospholipid antibodies Neuropsychiatric lupus Autoantibody 

Notes

Acknowledgements

MLB is funded by the Louise Gergel Fellowship. This study has not been supported by any specific funding.

Conflicts of interest

None. The authors declare no conflict of interest and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical standard

The study was conducted in accordance with the Helsinki Declaration.

References

  1. 1.
    Borchers AT, Aoki CA, Naguwa SM, Keen CL, Shoenfeld Y, Gershwin ME (2005) Neuropsychiatric features of systemic lupus erythematosus. Autoimmun Rev 4:329–344CrossRefPubMedGoogle Scholar
  2. 2.
    Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G (2011) Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum 41:1–11CrossRefPubMedGoogle Scholar
  3. 3.
    Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y (2012) Systemic lupus erythematosus one disease or many? Autoimmun Rev 11:593–595CrossRefPubMedGoogle Scholar
  4. 4.
    Kamm C, Zettl UK (2012) Autoimmune disorders affecting both the central and peripheral nervous system. Autoimmun Rev 11:196–202CrossRefPubMedGoogle Scholar
  5. 5.
    Zettl UK, Stuve O, Patejdl R (2012) Immune-mediated CNS diseases: a review on nosological classification and clinical features. Autoimmun Rev 11:167–173CrossRefPubMedGoogle Scholar
  6. 6.
    (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42(4):599–608Google Scholar
  7. 7.
    Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y (2004) Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34:501–537CrossRefPubMedGoogle Scholar
  8. 8.
    Zandman-Goddard G, Chapman J, Shoenfeld Y (2007) Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin Arthritis Rheum 36:297–315CrossRefPubMedGoogle Scholar
  9. 9.
    Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH (2002) Autoantibodies in neuropsychiatric lupus. Autoimmunity 35:79–86CrossRefPubMedGoogle Scholar
  10. 10.
    Galli M, Luciani D, Bertolini G, Barbui T (2003) Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 101:1827–1832CrossRefPubMedGoogle Scholar
  11. 11.
    Galli M, Luciani D, Bertolini G, Barbui T (2003) Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 102:2717–2723CrossRefPubMedGoogle Scholar
  12. 12.
    Lowry R (2013) Kappa as a measure of concordance in categorical sorting. http://vassarstats.net/kappa.html. Accessed May 28, 2013
  13. 13.
    Wells GASB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2013) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohrica/programs/clinical_epidemiology/oxfordasp. Accessed May 28, 2013
  14. 14.
    GRADE Working Group, GRADE profiler (2013) GRADEpro version. Available at: http://www.gradeworkinggrouporg/. Accessed April 5, 2013
  15. 15.
    Mok CC, Lau CS, Wong RW (2001) Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol 28:766–771PubMedGoogle Scholar
  16. 16.
    Brey RL, Holliday SL, Saklad AR et al (2002) Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 58:1214–1220CrossRefPubMedGoogle Scholar
  17. 17.
    Afeltra A, Garzia P, Mitterhofer AP et al (2003) Neuropsychiatric lupus syndromes: relationship with antiphospholipid antibodies. Neurology 61:108–110CrossRefPubMedGoogle Scholar
  18. 18.
    Sanna G, Bertolaccini ML, Cuadrado MJ et al (2003) Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 30:985–992PubMedGoogle Scholar
  19. 19.
    Houman MH, Smiti-Khanfir M, Ben Ghorbell I, Miled M (2004) Systemic lupus erythematosus in Tunisia: demographic and clinical analysis of 100 patients. Lupus 13:204–211CrossRefPubMedGoogle Scholar
  20. 20.
    Mikdashi J, Handwerger B (2004) Predictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology (Oxford) 43:1555–1560CrossRefGoogle Scholar
  21. 21.
    Mikdashi J, Krumholz A, Handwerger B (2005) Factors at diagnosis predict subsequent occurrence of seizures in systemic lupus erythematosus. Neurology 64:2102–2107CrossRefPubMedGoogle Scholar
  22. 22.
    Mok CC, To CH, Mak A (2006) Neuropsychiatric damage in Southern Chinese patients with systemic lupus erythematosus. Medicine (Baltimore) 85:221–228CrossRefGoogle Scholar
  23. 23.
    Harel L, Sandborg C, Lee T, von Scheven E (2006) Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies. J Rheumatol 33:1873–1877PubMedGoogle Scholar
  24. 24.
    Yu HH, Lee JH, Wang LC, Yang YH, Chiang BL (2006) Neuropsychiatric manifestations in pediatric systemic lupus erythematosus: a 20-year study. Lupus 15:651–657CrossRefPubMedGoogle Scholar
  25. 25.
    Hanly JG, Urowitz MB, Siannis F et al (2008) Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum 58:843–853CrossRefPubMedGoogle Scholar
  26. 26.
    Hanly JG, Urowitz MB, Su L et al (2011) Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis 70:1726–1732CrossRefPubMedGoogle Scholar
  27. 27.
    Hanly JG, Urowitz MB, Su L et al (2012) Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study. Ann Rheum Dis 71:1502–1509CrossRefPubMedGoogle Scholar
  28. 28.
    Kamen DL, Barron M, Parker TM et al (2008) Autoantibody prevalence and lupus characteristics in a unique African American population. Arthritis Rheum 58:1237–1247CrossRefPubMedGoogle Scholar
  29. 29.
    Singh S, Gupta MK, Ahluwalia J, Singh P, Malhi P (2009) Neuropsychiatric manifestations and antiphospholipid antibodies in pediatric onset lupus: 14 years of experience from a tertiary center of North India. Rheumatol Int 29:1455–1461CrossRefPubMedGoogle Scholar
  30. 30.
    Kozora E, Filley CM, Zhang L et al (2012) Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations. Lupus 21:402–411CrossRefPubMedGoogle Scholar
  31. 31.
    Borowoy AM, Pope JE, Silverman E et al (2012) Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort. Semin Arthritis Rheum 42:179–185CrossRefPubMedGoogle Scholar
  32. 32.
    Peretti CS, Peretti CR, Kozora E, Papathanassiou D, Chouinard VA, Chouinard G (2012) Cognitive impairment in systemic lupus erythematosus women with elevated autoantibodies and normal single photon emission computerized tomography. Psychother Psychosom 81:276–285CrossRefPubMedGoogle Scholar
  33. 33.
    Zirkzee EJ, Steup-Beekman GM, van der Mast RC et al (2012) Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy. J Rheumatol 39:2118–2126CrossRefPubMedGoogle Scholar
  34. 34.
    Abdel-Nasser AM, Ghaleb RM, Mahmoud JA, Khairy W, Mahmoud RM (2008) Association of anti-ribosomal P protein antibodies with neuropsychiatric and other manifestations of systemic lupus erythematosus. Clin Rheumatol 27:1377–1385CrossRefPubMedGoogle Scholar
  35. 35.
    Briani C, Lucchetta M, Ghirardello A et al (2009) Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study. J Autoimmun 32:79–84CrossRefPubMedGoogle Scholar
  36. 36.
    Gerli R, Caponi L, Tincani A et al (2002) Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients. Rheumatology (Oxford) 41:1357–1366CrossRefGoogle Scholar
  37. 37.
    Jarpa E, Babul M, Calderon J et al (2011) Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity. Lupus 20:58–66CrossRefPubMedGoogle Scholar
  38. 38.
    Yoshio T, Hirata D, Onda K, Nara H, Minota S (2005) Antiribosomal P protein antibodies in cerebrospinal fluid are associated with neuropsychiatric systemic lupus erythematosus. J Rheumatol 32:34–39PubMedGoogle Scholar
  39. 39.
    Karassa FB, Afeltra A, Ambrozic A et al (2006) Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. Arthritis Rheum 54:312–324CrossRefPubMedGoogle Scholar
  40. 40.
    Hanly JG, Robichaud J, Fisk JD (2006) Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol 33:1553–1558PubMedGoogle Scholar
  41. 41.
    Harrison MJ, Ravdin LD, Lockshin MD (2006) Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum 54:2515–2522CrossRefPubMedGoogle Scholar
  42. 42.
    Zavada J, Nytrova P, Wandinger KP et al (2011) Seroprevalence and specificity of NMO-IgG (anti-aquaporin 4 antibodies) in patients with neuropsychiatric systemic lupus erythematosus. Rheumatol Int 33:259–263CrossRefPubMedGoogle Scholar
  43. 43.
    Bhat NM, Lee LM, van Vollenhoven RF, Teng NN, Bieber MM (2002) VH4-34 encoded antibody in systemic lupus erythematosus: effect of isotype. J Rheumatol 29:2114–2121PubMedGoogle Scholar
  44. 44.
    Hanly JG, Urowitz MB, Su L et al (2008) Short-term outcome of neuropsychiatric events in systemic lupus erythematosus upon enrollment into an international inception cohort study. Arthritis Rheum 59:721–729CrossRefPubMedGoogle Scholar
  45. 45.
    Prasad R, Ibanez D, Gladman D, Urowitz M (2006) Anti-dsDNA and anti-Sm antibodies do not predict damage in systemic lupus erythematosus. Lupus 15:285–291CrossRefPubMedGoogle Scholar
  46. 46.
    Nazarinia MA, Ghaffarpasand F, Shamsdin A, Karimi AA, Abbasi N, Amiri A (2008) Systemic lupus erythematosus in the Fars Province of Iran. Lupus 17:221–227CrossRefPubMedGoogle Scholar
  47. 47.
    Yu HH, Wang LC, Lee JH, Lee CC, Yang YH, Chiang BL (2007) Lymphopenia is associated with neuropsychiatric manifestations and disease activity in paediatric systemic lupus erythematosus patients. Rheumatology (Oxford) 46:1492–1494CrossRefGoogle Scholar
  48. 48.
    Abdwani R, Rizvi SG, El-Nour I (2008) Childhood systemic lupus erythematosus in Sultanate of Oman: demographics and clinical analysis. Lupus 17:683–686CrossRefPubMedGoogle Scholar
  49. 49.
    Achour A, Mankai A, Thabet Y et al (2012) Systemic lupus erythematosus in the elderly. Rheumatol Int 32:1225–1229CrossRefPubMedGoogle Scholar
  50. 50.
    Adelowo OO, Oguntona SA (2009) Pattern of systemic lupus erythematosus among Nigerians. Clin Rheumatol 28:699–703CrossRefPubMedGoogle Scholar
  51. 51.
    Bruns A, Meyer O (2006) Neuropsychiatric manifestations of systemic lupus erythematosus. Jt Bone Spine 73:639–645CrossRefGoogle Scholar
  52. 52.
    Meszaros ZS, Perl A, Faraone SV (2012) Psychiatric symptoms in systemic lupus erythematosus: a systematic review. J Clin Psychiatry 73:993–1001CrossRefPubMedGoogle Scholar
  53. 53.
    Schenatto CB, Xavier RM, Bredemeier M et al (2006) Raised serum S100B protein levels in neuropsychiatric lupus. Ann Rheum Dis 65:829–831PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Yajima N, Kasama T, Isozaki T et al (2005) Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations. Arthritis Rheum 52:1670–1675CrossRefPubMedGoogle Scholar
  55. 55.
    Ainiala H, Hietaharju A, Dastidar P et al (2004) Increased serum matrix metalloproteinase 9 levels in systemic lupus erythematosus patients with neuropsychiatric manifestations and brain magnetic resonance imaging abnormalities. Arthritis Rheum 50:858–865CrossRefPubMedGoogle Scholar
  56. 56.
    Kumral E, Evyapan D, Keser G et al (2002) Detection of microembolic signals in patients with neuropsychiatric lupus erythematosus. Eur Neurol 47:131–135CrossRefPubMedGoogle Scholar
  57. 57.
    Gono T, Kawaguchi Y, Kaneko H et al (2011) Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 50:1578–1585CrossRefGoogle Scholar
  58. 58.
    Fragoso-Loyo H, Cabiedes J, Orozco-Narvaez A et al (2008) Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLoS One 3:e3347PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Lapteva L, Nowak M, Yarboro CH et al (2006) Anti-N-methyl-d-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum 54:2505–2514CrossRefPubMedGoogle Scholar
  60. 60.
    Zirkzee EJ, Steup-Beekman GM, van der Mast RC et al (2012) Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy. J Rheumatol 39:2118–2126CrossRefPubMedGoogle Scholar
  61. 61.
    Sanna G, Bertolaccini ML, Cuadrado MJ, Khamashta MA, Hughes GR (2003) Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford) 42:200–213CrossRefGoogle Scholar
  62. 62.
    Hanly JG, Urowitz MB, Su L et al (2012) Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study. Ann Rheum Dis 71(9):1502–1509CrossRefPubMedGoogle Scholar
  63. 63.
    Eber T, Chapman J, Shoenfeld Y (2005) Anti-ribosomal P-protein and its role in psychiatric manifestations of systemic lupus erythematosus: myth or reality? Lupus 14:571–575CrossRefPubMedGoogle Scholar
  64. 64.
    Elkon KB, Parnassa AP, Foster CL (1985) Lupus autoantibodies target ribosomal P proteins. J Exp Med 162:459–471CrossRefPubMedGoogle Scholar
  65. 65.
    Koffler D, Miller TE, Lahita RG (1979) Studies on the specificity and clinical correlation of antiribosomal antibodies in systemic lupus erythematosus sera. Arthritis Rheum 22:463–470CrossRefPubMedGoogle Scholar
  66. 66.
    Bonfa E, Elkon KB (1986) Clinical and serologic associations of the antiribosomal P protein antibody. Arthritis Rheum 29:981–985CrossRefPubMedGoogle Scholar
  67. 67.
    Bonfa E, Golombek SJ, Kaufman LD et al (1987) Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 30(317):265–271CrossRefGoogle Scholar
  68. 68.
    Isenberg D, Ramsey-Goldman R (2006) Systemic Lupus International Collaborating Group––onwards and upwards? Lupus 15:606–607CrossRefPubMedGoogle Scholar
  69. 69.
    DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7:1189–1193CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Savino Sciascia
    • 1
    • 2
  • Maria Laura Bertolaccini
    • 1
  • Dario Roccatello
    • 2
  • Munther A. Khamashta
    • 1
    • 3
  • Giovanni Sanna
    • 1
    • 3
    Email author
  1. 1.Graham Hughes Lupus Research Laboratory, Lupus Research Unit, Division of Women’s Health, The Rayne InstituteKing’s College London, 4th Floor Lambeth Wing, St Thomas’ HospitalLondonUK
  2. 2.Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID)Università di TorinoTurinItaly
  3. 3.Louise Coote Lupus UnitGuy’s and St Thomas’ NHS Foundation Trust, St Thomas’ HospitalLondonUK

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