Diagnosis and management of neuropsychiatric SLE

Journal name:
Nature Reviews Rheumatology
Volume:
10,
Pages:
338–347
Year published:
DOI:
doi:10.1038/nrrheum.2014.15
Published online

Abstract

Nervous system involvement in systemic lupus erythematosus (SLE) can manifest as a range of neurological and psychiatric features, which are classified using the ACR case definitions for 19 neuropsychiatric syndromes. Approximately one-third of all neuropsychiatric syndromes in patients with SLE are primary manifestations of SLE-related autoimmunity, with seizure disorders, cerebrovascular disease, acute confusional state and neuropathy being the most common. Such primary neuropsychiatric SLE (NPSLE) events are a consequence either of microvasculopathy and thrombosis, or of autoantibodies and inflammatory mediators. Diagnosis of NPSLE requires the exclusion of other causes, and clinical assessment directs the selection of appropriate investigations. These investigations include measurement of autoantibodies, analysis of cerebrospinal fluid, electrophysiological studies, neuropsychological assessment and neuroimaging to evaluate brain structure and function. Treatment involves the management of comorbidities contributing to the neuropsychiatric event, use of symptomatic therapies, and more specific interventions with either anticoagulation or immunosuppressive agents, depending upon the primary immunopathogenetic mechanism. Although the prognosis is variable, studies suggest a more favourable outcome for primary NPSLE manifestations compared with neuropsychiatric events attributable to non-SLE causes.

At a glance

Figures

  1. Factors contributing to neuropsychiatric events in patients with SLE.
    Figure 1: Factors contributing to neuropsychiatric events in patients with SLE.

    Focal and diffuse nervous system events can result from autoimmune or inflammatory mechanisms directly related to SLE (primary NPSLE), as a consequence of complications of the disease (for example, uraemia or hypertension) or its therapy (for example, infection) (secondary NPSLE), or as a concurrent neuropsychiatric event unrelated to SLE. Abbreviations: +, minor contribution to NPSLE; ++, moderate contribution to NPSLE; +++, substantial contribution to NPSLE; aPL, antiphospholipid antibodies; NPSLE, neuropsychiatric SLE; SLE, systemic lupus erythematosus. Adapted with permission from Springer © Hanly, J. G. Curr. Rheumatol. Rep. 3, 205212 (2001).

  2. Negative effect of NP events on HRQoL in patients with SLE.
    Figure 2: Negative effect of NP events on HRQoL in patients with SLE.22

    The difference in HRQoL of patients newly diagnosed with SLE with and without NP events is indicated by SF-36 subscale scores (upper panel) and physical and mental composite scores (lower panel), expressed as means ±SEM. Those patients with NP events, regardless of attribution to SLE or non-SLE causes, had consistently lower scores, indicating poorer HRQoL. Abbreviations: HRQoL, health-related quality of life; NP, neuropsychiatric; SF-36, short form 36; SLE, systemic lupus erythematosus. Reproduced with permission from John Wiley & Sons, Inc. © Hanly, J. G. et al. Arthritis Rheum. 56, 265273 (2007).22

  3. Autoimmune pathogenesis of NPSLE.
    Figure 3: Autoimmune pathogenesis of NPSLE.

    Vascular injury involving both large and small-calibre vessels is mediated by aPL, immune complexes and leukoagglutination, and can result in focal neuropsychiatric events (for example, stroke) or diffuse neuropsychiatric events (for example, cognitive dysfunction). Inflammatory injury, involving increased permeability of the BBB, formation of immune complexes and production of IFN-α and other inflammatory mediators, can lead to diffuse neuropsychiatric manifestations (for example, psychosis, acute confusional states). Abbreviations: aPL, antiphospholipid antibodies; BBB, blood–brain barrier; MMP, matrix metalloproteinase; NPSLE, neuropsychiatric systemic lupus erythematosus; pDC, plasmacytoid dendritic cell.

  4. Physician-generated outcome scores for NP events at enrolment into an international inception cohort of patients with SLE.
    Figure 4: Physician-generated outcome scores for NP events at enrolment into an international inception cohort of patients with SLE.23

    NP events were attributed to SLE or non-SLE causes using one of two different attribution models. Using attribution model A, the NP event was attributed to SLE unless onset of NP events occurred before the study enrolment window, non-SLE factors that contributed to or were responsible for the NP event were identified, or NP events with a high frequency in the general population (as defined by Ainiala et al.5) occurred. Using attribution model B, the NP event was attributed to SLE unless onset of NP events occurred >10 years before the diagnosis of SLE, non-SLE factors responsible for the NP event were identified, or NP events with a high frequency in the general population (as defined by Ainiala et al.5) occurred. Those NP events that were attributed to SLE using either model A or model B had a significantly better outcome than NP events not attributed to SLE (P <0.001). Abbreviations: NP, neuropsychiatric; SLE, systemic lupus erythematosus. Reproduced with permission from John Wiley & Sons, Inc. © Hanly, J. G. et al. Arthritis Care Res. 59, 721729 (2008).23

References

  1. Gladman, D. & Urowitz, M. B. in Rheumatology (ed. Hochberg, M. C.) 13591380 (Mosby, Toronto, 2003).
  2. Cervera, R. et al. Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 78, 167175 (1999).
  3. Jacobsen, S. et al. Mortality and causes of death of 513 Danish patients with systemic lupus erythematosus. Scand. J. Rheumatol. 28, 7580 (1999).
  4. Urowitz, M. B., Gladman, D. D., Abu-Shakra, M. & Farewell, V. T. Mortality studies in systemic lupus erythematosus. Results from a single center. III. Improved survival over 24 years. J. Rheumatol. 24, 10611065 (1997).
  5. Ainiala, H. et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum. 45, 419423 (2001).
  6. Brey, R. L. et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 58, 12141220 (2002).
  7. Hanly, J. G., McCurdy, G., Fougere, L., Douglas, J. A. & Thompson, K. Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance. J. Rheumatol. 31, 21562162 (2004).
  8. Sanna, G. et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J. Rheumatol. 30, 985992 (2003).
  9. Sibbitt, W. L. Jr et al. The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus. J. Rheumatol. 29, 15361542 (2002).
  10. Boumpas, D. T. et al. Systemic lupus erythematosus: emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann. Intern. Med. 122, 940950 (1995).
  11. Sergent, J. S., Lockshin, M. D., Klempner, M. S. & Lipsky, B. A. Central nervous system disease in systemic lupus erythematosus. Therapy and prognosis. Am. J. Med. 58, 644654 (1975).
  12. Ainiala, H., Loukkola, J., Peltola, J., Korpela, M. & Hietaharju, A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 57, 496500 (2001).
  13. Estes, D. & Christian, C. L. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 50, 8595 (1971).
  14. Ginzler, E. M. et al. A multicenter study of outcome in systemic lupus erythematosus. I. Entry variables as predictors of prognosis. Arthritis Rheum. 25, 601611 (1982).
  15. Lee, P. et al. Systemic lupus erythematosus. A review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis. Q. J. Med. 46, 132 (1977).
  16. Bernatsky, S. et al. Mortality related to cerebrovascular disease in systemic lupus erythematosus. Lupus 15, 835839 (2006).
  17. Sibley, J. T., Olszynski, W. P., Decoteau, W. E. & Sundaram, M. B. The incidence and prognosis of central nervous system disease in systemic lupus erythematosus. J. Rheumatol. 19, 4752 (1992).
  18. Feinglass, E. J., Arnett, F. C., Dorsch, C. A., Zizic, T. M. & Stevens, M. B. Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine (Baltimore) 55, 323339 (1976).
  19. Kovacs, J. A., Urowitz, M. B. & Gladman, D. D. Dilemmas in neuropsychiatric lupus. Rheum. Dis. Clin. North Am. 19, 795814 (1993).
  20. [No authors listed] The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 42, 599608 (1999).
  21. Hanly, J. G. et al. Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum. 58, 843853 (2008).
  22. Hanly, J. G. et al. Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study. Arthritis Rheum. 56, 265273 (2007).
  23. Hanly, J. G. et al. Short-term outcome of neuropsychiatric events in systemic lupus erythematosus upon enrollment into an international inception cohort study. Arthritis Rheum. 59, 721729 (2008).
  24. Hanly, J. G. et al. Prospective study of neuropsychiatric events in systemic lupus erythematosus. J. Rheumatol. 36, 14491459 (2009).
  25. Hanly, J. G. et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann. Rheum. Dis. 69, 529535 (2010).
  26. Hanly, J. G., Su, L., Omisade, A., Farewell, V. T. & Fisk, J. D. Screening for cognitive impairment in systemic lupus erythematosus. J. Rheumatol. 39, 13711377 (2012).
  27. Hanly, J. G. in Systemic Lupus Erythematosus, 5th edn (ed. Lahita, R. G.) 727746 (Elsevier, 2011).
  28. Denburg, S. D. & Denburg, J. A. Cognitive dysfunction and antiphospholipid antibodies in systemic lupus erythematosus. Lupus 12, 883890 (2003).
  29. Hanly, J. G. & Liang, M. H. Cognitive disorders in systemic lupus erythematosus. Epidemiologic and clinical issues. Ann. NY Acad. Sci. 823, 6068 (1997).
  30. Ellis, S. G. & Verity, M. A. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955–1977. Semin. Arthritis Rheum. 8, 212221 (1979).
  31. Johnson, R. T. & Richardson, E. P. The neurological manifestations of systemic lupus erythematosus. Medicine (Baltimore) 47, 337369 (1968).
  32. Weiner, S. M., Klein, R. & Berg, P. A. A longitudinal study of autoantibodies against central nervous system tissue and gangliosides in connective tissue diseases. Rheumatol. Int. 19, 8388 (2000).
  33. Bluestein, H. G., Williams, G. W. & Steinberg, A. D. Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am. J. Med. 70, 240246 (1981).
  34. Zvaifler, N. J. & Bluestein, H. G. The pathogenesis of central nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum. 25, 862866 (1982).
  35. Martinez-Cordero, E., Rivera Garcia, B. E. & Aguilar Leon, D. E. Anticardiolipin antibodies in serum and cerebrospinal fluid from patients with systemic lupus erythematosus. J. Investig. Allergol. Clin. Immunol. 7, 596601 (1997).
  36. Gono, T. et al. NR2-reactive antibody decreases cell viability through augmentation of Ca2+ influx in systemic lupus erythematosus. Arthritis Rheum. 63, 39523959 (2011).
  37. DeGiorgio, L. A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 11891193 (2001).
  38. Kowal, C. et al. Cognition and immunity: antibody impairs memory. Immunity 21, 179188 (2004).
  39. Lauvsnes, M. B. & Omdal, R. Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. J. Neurol. 259, 622629 (2012).
  40. Yoshio, T., Onda, K., Nara, H. & Minota, S. Association of IgG anti-NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 54, 675678 (2006).
  41. Arinuma, Y., Yanagida, T. & Hirohata, S. Association of cerebrospinal fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 58, 11301135 (2008).
  42. Bonfa, E. et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N. Engl. J. Med 317, 265271 (1987).
  43. Briani, C. et al. Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study. J. Autoimmun. 32, 7984 (2009).
  44. Hirohata, S., Arinuma, Y., Takayama, M. & Yoshio, T. Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Arthritis Res. Ther. 9, R44 (2007).
  45. Karassa, F. B. et al. Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. Arthritis Rheum. 54, 312324 (2006).
  46. Teh, L. S. & Isenberg, D. A. Antiribosomal P protein antibodies in systemic lupus erythematosus. A reappraisal. Arthritis Rheum. 37, 307315 (1994).
  47. Hanly, J. G. et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 17261732 (2011).
  48. Hanly, J. G. Antiphospholipid syndrome: an overview. CMAJ 168, 16751682 (2003).
  49. Musial, J. Antiphospholipid antibodies and thrombosis. Thromb. Res. 129, 345347 (2012).
  50. Love, P. E. & Santoro, S. A. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann. Intern. Med. 112, 682698 (1990).
  51. Menon, S. et al. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum. 42, 735741 (1999).
  52. Hanly, J. G., Hong, C., Smith, S. & Fisk, J. D. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum. 42, 728734 (1999).
  53. Chapman, J., Cohen-Armon, M., Shoenfeld, Y. & Korczyn, A. D. Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus 8, 127133 (1999).
  54. Hirohata, S. & Miyamoto, T. Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum. 33, 644649 (1990).
  55. Shiozawa, S., Kuroki, Y., Kim, M., Hirohata, S. & Ogino, T. Interferon-α in lupus psychosis. Arthritis Rheum. 35, 417422 (1992).
  56. Jara, L. J. et al. Prolactin and interleukin-6 in neuropsychiatric lupus erythematosus. Clin. Rheumatol. 17, 110114 (1998).
  57. Hirohata, S. & Hayakawa, K. Enhanced interleukin-6 messenger RNA expression by neuronal cells in a patient with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 42, 27292730 (1999).
  58. Trysberg, E., Carlsten, H. & Tarkowski, A. Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 9, 498503 (2000).
  59. Rood, M. J. et al. Neuropsychiatric systemic lupus erythematosus is associated with imbalance in interleukin 10 promoter haplotypes. Ann. Rheum. Dis. 58, 8589 (1999).
  60. Gilad, R., Lampl, Y., Eshel, Y., Barak, V. & Sarova-Pinhas, I. Cerebrospinal fluid soluble interleukin-2 receptor in cerebral lupus. Br. J. Rheumatol. 36, 190193 (1997).
  61. Santer, D. M., Yoshio, T., Minota, S., Moller, T. & Elkon, K. B. Potent induction of IFN-α and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J. Immunol. 182, 11921201 (2009).
  62. 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) 50, 21422144 (2011).
  63. Hanly, J. G. New insights into central nervous system lupus: a clinical perspective. Curr. Rheumatol. Rep. 9, 116124 (2007).
  64. Bertsias, G. K. et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann. Rheum. Dis. 69, 20742082 (2010).
  65. Esdaile, J. M. et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 44, 23312337 (2001).
  66. Urowitz, M. B. et al. Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 62, 881887 (2010).
  67. Govoni, M. et al. Factors and comorbidities associated with first neuropsychiatric event in systemic lupus erythematosus: does a risk profile exist? A large multicentre retrospective cross-sectional study on 959 Italian patients. Rheumatology (Oxford) 51, 157168 (2012).
  68. Florica, B. et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin. Arthritis Rheum. 41, 203211 (2011).
  69. Toledano, P., Sarbu, N., Espinosa, G., Bargallo, N. & Cervera, R. Neuropsychiatric systemic lupus erythematosus: magnetic resonance imaging findings and correlation with clinical and immunological features. Autoimmun. Rev. 12, 11661170 (2013).
  70. Jarpa, E. et al. Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity. Lupus 20, 5866 (2011).
  71. Shimojima, Y., Matsuda, M., Gono, T., Ishii, W. & Ikeda, S. Relationship between clinical factors and neuropsychiatric manifestations in systemic lupus erythematosus. Clin. Rheumatol. 24, 469475 (2005).
  72. Omdal, R. et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur. J. Neurol. 12, 392398 (2005).
  73. Lapteva, L. et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum. 54, 25052514 (2006).
  74. Hanly, J. G., Robichaud, J. & Fisk, J. D. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J. Rheumatol. 33, 15531558 (2006).
  75. Harrison, M. J., Ravdin, L. D. & Lockshin, M. D. Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum. 54, 25152522 (2006).
  76. Steup-Beekman, G., Steens, S., van Buchem, M. & Huizinga, T. Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 16, 329334 (2007).
  77. Birnbaum, J. & Kerr, D. Devic's syndrome in a woman with systemic lupus erythematosus: diagnostic and therapeutic implications of testing for the neuromyelitis optica IgG autoantibody. Arthritis Rheum. 57, 347351 (2007).
  78. Waters, P. et al. Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch. Neurol. 65, 913919 (2008).
  79. Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S. & Hinson, S. R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473477 (2005).
  80. Vieira-Karuta, S. C. et al. Epileptic seizures and EEG features in juvenile systemic lupus erythematosus. Arq. Neuropsiquiatr. 66, 468470 (2008).
  81. Alarcon, G. S. et al. Systemic lupus erythematosus in three ethnic groups. X. Measuring cognitive impairment with the cognitive symptoms inventory. Arthritis Rheum. 47, 310319 (2002).
  82. Julian, L. J. et al. Validity of brief screening tools for cognitive impairment in rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 64, 448454 (2012).
  83. Hanly, J. G., Omisade, A., Su, L., Farewell, V. & Fisk, J. D. Assessment of cognitive function in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by computerized neuropsychological tests. Arthritis Rheum. 62, 14781486 (2010).
  84. Sibbitt, W. L., Jr, Sibbitt, R. R. & Brooks, W. M. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 42, 20262038 (1999).
  85. Peterson, P. L., Howe, F. A., Clark, C. A. & Axford, J. S. Quantitative magnetic resonance imaging in neuropsychiatric systemic lupus erythematosus. Lupus 12, 897902 (2003).
  86. Appenzeller, S., Pike, G. B. & Clarke, A. E. Magnetic resonance imaging in the evaluation of central nervous system manifestations in systemic lupus erythematosus. Clin. Rev. Allergy Immunol. 34, 361366 (2008).
  87. Rovaris, M. et al. Brain involvement in systemic immune mediated diseases: magnetic resonance and magnetisation transfer imaging study. J. Neurol. Neurosurg. Psychiatry 68, 170177 (2000).
  88. Graham, J. W. & Jan, W. MRI and the brain in systemic lupus erythematosus. Lupus 12, 891896 (2003).
  89. Hanly, J. G. Evaluation of patients with CNS involvement in SLE. Baillieres Clin. Rheumatol. 12, 415431 (1998).
  90. Nossent, J. C., Hovestadt, A., Schonfeld, D. H. & Swaak, A. J. Single-photon-emission computed tomography of the brain in the evaluation of cerebral lupus. Arthritis Rheum. 34, 13971403 (1991).
  91. Oku, K. et al. Cerebral imaging by magnetic resonance imaging and single photon emission computed tomography in systemic lupus erythematosus with central nervous system involvement. Rheumatology (Oxford) 42, 773777 (2003).
  92. Rubbert, A. et al. Single-photon-emission computed tomography analysis of cerebral blood flow in the evaluation of central nervous system involvement in patients with systemic lupus erythematosus. Arthritis Rheum. 36, 12531262 (1993).
  93. Rogers, M. P. et al. I-123 iofetamine SPECT scan in systemic lupus erythematosus patients with cognitive and other minor neuropsychiatric symptoms: a pilot study. Lupus 1, 215219 (1992).
  94. Kovacs, J. A., Urowitz, M. B., Gladman, D. D. & Zeman, R. The use of single photon emission computerized tomography in neuropsychiatric SLE: a pilot study. J. Rheumatol. 22, 12471253 (1995).
  95. Waterloo, K. et al. Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow. J. Neurol. 248, 595602 (2001).
  96. Fitzgibbon, B. M. et al. Functional MRI in NPSLE patients reveals increased parietal and frontal brain activation during a working memory task compared with controls. Rheumatology (Oxford) 47, 5053 (2008).
  97. DiFrancesco, M. W. et al. Functional magnetic resonance imaging assessment of cognitive function in childhood-onset systemic lupus erythematosus: a pilot study. Arthritis Rheum. 56, 41514163 (2007).
  98. Barile-Fabris, L. et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann. Rheum. Dis. 64, 620625 (2005).
  99. Fernandez, M., Trevisani, V. F., Castro, A. A., Neves Neto, J. F. & Atallah, A. N. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD002265. http://dx.doi.org/10.1002/14651858.CD002265.pub3.
  100. Mok, C. C., Lau, C. S. & Wong, R. W. Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study. Am. J. Med. 115, 5962 (2003).
  101. Tokunaga, M. et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann. Rheum. Dis. 66, 470475 (2007).
  102. Finazzi, G. et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J. Thromb. Haemost. 3, 848853 (2005).
  103. Crowther, M. A. et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N. Engl. J. Med. 349, 11331138 (2003).
  104. Ruiz-Irastorza, G., Hunt, B. J. & Khamashta, M. A. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 57, 14871495 (2007).
  105. Jung, H. et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 62, 863868 (2010).
  106. Meroni, P. L. et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-β2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 44, 28702878 (2001).
  107. Denburg, S. D., Carbotte, R. M. & Denburg, J. A. Corticosteroids and neuropsychological functioning in patients with systemic lupus erythematosus. Arthritis Rheum. 37, 13111320 (1994).
  108. Petri, M., Naqibuddin, M., Sampedro, M., Omdal, R. & Carson, K. A. Memantine in systemic lupus erythematosus: a randomized, double-blind placebo-controlled trial. Semin. Arthritis Rheum. 41, 194202 (2011).
  109. Harrison, M. J. et al. Results of intervention for lupus patients with self-perceived cognitive difficulties. Neurology 65, 13251327 (2005).
  110. Karlson, E. W. et al. A randomized clinical trial of a psychoeducational intervention to improve outcomes in systemic lupus erythematosus. Arthritis Rheum. 50, 18321841 (2004).
  111. McCune, W. J. et al. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N. Engl. J. Med. 318, 14231431 (1988).
  112. Hanly, J. G., Cassell, K. & Fisk, J. D. Cognitive function in systemic lupus erythematosus: results of a 5-year prospective study. Arthritis Rheum. 40, 15421543 (1997).
  113. Waterloo, K., Omdal, R., Husby, G. & Mellgren, S. I. Neuropsychological function in systemic lupus erythematosus: a five-year longitudinal study. Rheumatology (Oxford) 41, 411415 (2002).
  114. Karassa, F. B. et al. Predictors of clinical outcome and radiologic progression in patients with neuropsychiatric manifestations of systemic lupus erythematosus. Am. J. Med. 109, 628634 (2000).
  115. Boers, M. Understanding the window of opportunity concept in early rheumatoid arthritis. Arthritis Rheum. 48, 17711774 (2003).
  116. Cush, J. J. Early rheumatoid arthritis—is there a window of opportunity? J. Rheumatol. 80 (Suppl.), 17 (2007).

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  1. Division of Rheumatology, Department of Medicine and Department of Pathology, Capital Health and Dalhousie University, Halifax, NS B3H 4K4, Canada.

    • John G. Hanly

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  • John G. Hanly

    John G. Hanly is Professor of Medicine and Pathology and Director of the Dalhousie Lupus Clinic in the Division of Rheumatology, Department of Medicine, at Dalhousie University and Queen Elizabeth II Health Sciences Center in Halifax, Nova Scotia, Canada. His research interests include the study of disease mechanisms, prognosis and treatment of patients with systemic lupus erythematosus, and he has a particular interest in nervous system manifestations of SLE.

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