Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neuropsychiatric lupus: new mechanistic insights and future treatment directions

Nature Reviews Rheumatology volume 15, pages 137–152 (2019)Cite this article

Subjects

Abstract

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood–brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.

Key points

  • Management of neuropsychiatric symptoms in patients with systemic lupus erythematosus (SLE) remains challenging as evidence-based regimens are not generally available.

  • A pressing need in the management of neuropsychiatric SLE (NPSLE) is the appropriate attribution of symptoms to either primary inflammatory pathology or secondary consequences of the general SLE disease burden.

  • Research efforts are aggressively pursuing the identification of pathways involved in NPSLE development, along with new therapeutic targets.

  • Mechanisms at the neuroimmune interface are being studied and might extend beyond the cerebral circulation and the blood–brain barrier to include the blood–cerebrospinal fluid barrier and/or the meningeal barrier.

  • Novel therapies, including small-molecule inhibitors and biologic agents that target inflammatory pathways, are currently being explored to target NPSLE specifically.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Neuroimmune interfaces and postulated mechanisms by which they can be breached.
Fig. 2: Pathogenetic mechanisms and potential treatment targets in diffuse NPSLE.

Similar content being viewed by others

References

  1. Unterman, A. et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin. Arthritis Rheum. 41, 1–11 (2011).

    PubMed  Google Scholar 

  2. Ainiala, H., Loukkola, J., Peltola, J., Korpela, M. & Hietaharju, A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 57, 496–500 (2001).

    CAS  PubMed  Google Scholar 

  3. Bertsias, G. K. & Boumpas, D. T. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat. Rev. Rheumatol. 6, 358–367 (2010).

    PubMed  Google Scholar 

  4. Borowoy, A. M. et al. Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 Faces of Lupus cohort. Semin. Arthritis Rheum. 42, 179–185 (2012).

    PubMed  Google Scholar 

  5. Kozora, E. et al. Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations. Lupus 21, 402–411 (2012).

    CAS  PubMed  Google Scholar 

  6. The American College of Rheumatology. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 42, 599–608 (1999).

    Google Scholar 

  7. 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, 529–535 (2010).

    CAS  PubMed  Google Scholar 

  8. Mok, C. C., Lau, C. S. & Wong, R. W. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J. Rheumatol. 28, 766–771 (2001).

    CAS  PubMed  Google Scholar 

  9. Ho, R. C. et al. A meta-analysis of serum and cerebrospinal fluid autoantibodies in neuropsychiatric systemic lupus erythematosus. Autoimmun. Rev. 15, 124–138 (2016).

    CAS  PubMed  Google Scholar 

  10. Steup-Beekman, G. M. et al. Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause. Ann. Rheum. Dis. 72 (Suppl. 2), ii76–ii79 (2013).

    CAS  PubMed  Google Scholar 

  11. Bujan, S. et al. Contribution of the initial features of systemic lupus erythematosus to the clinical evolution and survival of a cohort of Mediterranean patients. Ann. Rheum. Dis. 62, 859–865 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 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, 157–168 (2012).

    Google Scholar 

  13. Govoni, M. et al. The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J. Autoimmun. 74, 41–72 (2016).

    CAS  PubMed  Google Scholar 

  14. Hanly, J. G. et al. Cerebrovascular events in systemic lupus erythematosus: results from an international inception cohort study. Arthritis Care Res. 70, 1478–1487 (2018).

    Google Scholar 

  15. Mikdashi, J. & Handwerger, B. Predictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology (Oxford) 43, 1555–1560 (2004).

    CAS  Google Scholar 

  16. Brey, R. L., Gharavi, A. E. & Lockshin, M. D. Neurologic complications of antiphospholipid antibodies. Rheum. Dis. Clin. North Am. 19, 833–850 (1993).

    CAS  PubMed  Google Scholar 

  17. 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, 212–221 (1979).

    CAS  PubMed  Google Scholar 

  18. Hanly, J. G. et al. Prospective study of neuropsychiatric events in systemic lupus erythematosus. J. Rheumatol. 36, 1449–1459 (2009).

    PubMed  Google Scholar 

  19. 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, 2074–2082 (2010).

    CAS  PubMed  Google Scholar 

  20. Cohen, D. et al. Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology (Oxford) 56, 77–86 (2017).

    CAS  Google Scholar 

  21. Luyendijk, J. et al. Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging. Arthritis Rheum. 63, 722–732 (2011).

    CAS  PubMed  Google Scholar 

  22. Hanly, J. G., Kozora, E., Beyea, S. & Birnbaum, J. Nervous system disease in systemic lupus erythematosus: current status and future directions. Arthritis Rheumatol. 71, 33–42 (2018).

    Article  PubMed  Google Scholar 

  23. Bortoluzzi, A., Scire, C. A. & Govoni, M. Attribution of neuropsychiatric manifestations to systemic lupus erythematosus. Front. Med. 5, 68 (2018).

    Google Scholar 

  24. Hanly, J. G. et al. Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study. Arthritis Rheum. 56, 265–273 (2007).

    CAS  PubMed  Google Scholar 

  25. 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, 721–729 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bortoluzzi, A. et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford) 54, 891–898 (2015).

    CAS  Google Scholar 

  27. Magro-Checa, C. et al. Value of multidisciplinary reassessment in attribution of neuropsychiatric events to systemic lupus erythematosus: prospective data from the Leiden NPSLE cohort. Rheumatology (Oxford) 56, 1676–1683 (2017).

    Google Scholar 

  28. Castillo-Gomez, E. et al. All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. Mol. Psychiatry 22, 1776–1784 (2017).

    CAS  PubMed  Google Scholar 

  29. Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl Acad. Sci. USA 103, 19854–19859 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bravo-Zehnder, M. et al. Anti-ribosomal P protein autoantibodies from patients with neuropsychiatric lupus impair memory in mice. Arthritis Rheumatol. 67, 204–214 (2015).

    CAS  PubMed  Google Scholar 

  31. Du, Y., Sanam, S., Kate, K. & Mohan, C. Animal models of lupus and lupus nephritis. Curr. Pharm. Des. 21, 2320–2349 (2015).

    CAS  PubMed  Google Scholar 

  32. Kier, A. B. Clinical neurology and brain histopathology in NZB/NZW F1 lupus mice. J. Comp. Pathol. 102, 165–177 (1990).

    CAS  PubMed  Google Scholar 

  33. Leung, J. W., Lau, B. W., Chan, V. S., Lau, C. S. & So, K. F. Abnormal increase of neuronal precursor cells and exacerbated neuroinflammation in the corpus callosum in murine model of systemic lupus erythematosus. Restor. Neurol. Neurosci. 34, 443–453 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ballok, D. A. Neuroimmunopathology in a murine model of neuropsychiatric lupus. Brain Res. Rev. 54, 67–79 (2007).

    CAS  PubMed  Google Scholar 

  35. Williams, S., Stafford, P. & Hoffman, S. A. Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays. BMC Immunol. 15, 23 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Han, J. H. et al. Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression. Eur. J. Immunol. 44, 215–226 (2014).

    CAS  PubMed  Google Scholar 

  37. McDonald, G. et al. Accelerated systemic autoimmunity in the absence of somatic hypermutation in 564Igi: a mouse model of systemic lupus with knocked-in heavy and light chain genes. Front. Immunol. 8, 1094 (2017).

    PubMed  PubMed Central  Google Scholar 

  38. Bialas, A. R. et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 546, 539–543 (2017).

    CAS  PubMed  Google Scholar 

  39. Shi, D. et al. FTY720 attenuates behavioral deficits in a murine model of systemic lupus erythematosus. Brain Behav. Immun. 70, 293–304 (2018).

    CAS  PubMed  Google Scholar 

  40. de Amorim, L. C., Maia, F. M. & Rodrigues, C. E. Stroke in systemic lupus erythematosus and antiphospholipid syndrome: risk factors, clinical manifestations, neuroimaging, and treatment. Lupus 26, 529–536 (2017).

    PubMed  Google Scholar 

  41. Sarbu, N. et al. Brain abnormalities in newly diagnosed neuropsychiatric lupus: systematic MRI approach and correlation with clinical and laboratory data in a large multicenter cohort. Autoimmun. Rev. 14, 153–159 (2015).

    PubMed  Google Scholar 

  42. Merali, Z., Huang, K., Mikulis, D., Silver, F. & Kassner, A. Evolution of blood–brain-barrier permeability after acute ischemic stroke. PLOS ONE 12, e0171558 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. Kuntz, M. et al. Stroke-induced brain parenchymal injury drives blood–brain barrier early leakage kinetics: a combined in vivo/in vitro study. J. Cereb. Blood Flow Metab. 34, 95–107 (2014).

    PubMed  Google Scholar 

  44. Knowland, D. et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82, 603–617 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rochfort, K. D. & Cummins, P. M. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem. Soc. Trans. 43, 702–706 (2015).

    CAS  PubMed  Google Scholar 

  46. Dimitrijevic, O. B., Stamatovic, S. M., Keep, R. F. & Andjelkovic, A. V. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38, 1345–1353 (2007).

    CAS  PubMed  Google Scholar 

  47. Yepes, M. et al. A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. Am. J. Pathol. 166, 511–520 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Salahuddin, T. S., Kalimo, H., Johansson, B. B. & Olsson, Y. Observations on exudation of fibronectin, fibrinogen and albumin in the brain after carotid infusion of hyperosmolar solutions. An immunohistochemical study in the rat indicating long-lasting changes in the brain microenvironment and multifocal nerve cell injuries. Acta Neuropathol. 76, 1–10 (1988).

    CAS  PubMed  Google Scholar 

  49. Wen, J. et al. TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice. J. Autoimmun. 60, 40–50 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Fragoso-Loyo, H. et al. Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLOS ONE 3, e3347 (2008).

    PubMed  PubMed Central  Google Scholar 

  51. Omdal, R. et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur. J. Neurol. 12, 392–398 (2005).

    CAS  PubMed  Google Scholar 

  52. Hirohata, S., Arinuma, Y., Yanagida, T. & Yoshio, T. Blood-brain barrier damages and intrathecal synthesis of anti-N-methyl-D-aspartate receptor NR2 antibodies in diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Arthritis Res. Ther. 16, R77 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Hirohata, S., Sakuma, Y., Yanagida, T. & Yoshio, T. Association of cerebrospinal fluid anti-Sm antibodies with acute confusional state in systemic lupus erythematosus. Arthritis Res. Ther. 16, 450 (2014).

    PubMed  PubMed Central  Google Scholar 

  54. Bonfa, E. et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N. Engl. J. Med. 317, 265–271 (1987).

    CAS  PubMed  Google Scholar 

  55. Schneebaum, A. B. et al. Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am. J. Med. 90, 54–62 (1991).

    CAS  PubMed  Google Scholar 

  56. Nojima, Y. et al. Correlation of antibodies to ribosomal P protein with psychosis in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 51, 1053–1055 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hammer, C. et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol. Psychiatry 19, 1143–1149 (2014).

    CAS  PubMed  Google Scholar 

  58. Huerta, P. T., Kowal, C., DeGiorgio, L. A., Volpe, B. T. & Diamond, B. Immunity and behavior: antibodies alter emotion. Proc. Natl Acad. Sci. USA 103, 678–683 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kowal, C. et al. Cognition and immunity; antibody impairs memory. Immunity 21, 179–188 (2004).

    CAS  PubMed  Google Scholar 

  60. Lapteva, L. et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum. 54, 2505–2514 (2006).

    CAS  PubMed  Google Scholar 

  61. Tumani, H., Huss, A. & Bachhuber, F. The cerebrospinal fluid and barriers - anatomic and physiologic considerations. Handb. Clin. Neurol. 146, 21–32 (2017).

    PubMed  Google Scholar 

  62. Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).

    PubMed  PubMed Central  Google Scholar 

  63. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Baizabal-Carvallo, J. F., Delgadillo-Marquez, G., Estanol, B. & Garcia-Ramos, G. Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus. Eur. Neurol. 61, 143–148 (2009).

    PubMed  Google Scholar 

  65. Kakati, S., Barman, B., Ahmed, S. U. & Hussain, M. Neurological manifestations in systemic lupus erythematosus: a single centre study from North East India. J. Clin. Diagn. Res. 11, OC05–OC09 (2017).

    PubMed  PubMed Central  Google Scholar 

  66. Yelehe-Okouma, M., Czmil-Garon, J., Pape, E., Petitpain, N. & Gillet, P. Drug-induced aseptic meningitis: a mini-review. Fund. Clin. Pharmacol. 32, 252–260 (2018).

    CAS  Google Scholar 

  67. van Veen, K. E. B., Brouwer, M. C., van der Ende, A. & van de Beek, D. Bacterial meningitis in patients using immunosuppressive medication: a population-based prospective nationwide study. J. Neuroimmune Pharmacol. 12, 213–218 (2017).

    PubMed  Google Scholar 

  68. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523 (2009).

    CAS  PubMed  Google Scholar 

  69. Baruch, K. et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Atkins, C. J., Kondon, J. J., Quismorio, F. P. & Friou, G. J. The choroid plexus in systemic lupus erythematosus. Ann. Intern. Med. 76, 65–72 (1972).

    CAS  PubMed  Google Scholar 

  71. Sher, J. H. & Pertschuk, L. P. Immunoglobulin G deposits in the choroid plexus of a child with systemic lupus erythematosus. J. Pediatr. 85, 385–387 (1974).

    CAS  PubMed  Google Scholar 

  72. Gershwin, M. E., Hyman, L. R. & Steinberg, A. D. The choroid plexus in CNS involvement of systemic lupus erythematosus. J. Pediatr. 87, 588–590 (1975).

    CAS  PubMed  Google Scholar 

  73. Boyer, R. S., Sun, N. C., Verity, A., Nies, K. M. & Louie, J. S. Immunoperoxidase staining of the choroid plexus in systemic lupus erythematosus. J. Rheumatol. 7, 645–650 (1980).

    CAS  PubMed  Google Scholar 

  74. Amaro, E. Jr & Scheinberg, M. Onset of cognitive dysfunction in systemic lupus erythematosus and selective involvement of the choroid plexus. J. Rheumatol. 36, 2554–2555 (2009).

    PubMed  Google Scholar 

  75. Stock, A., Wen, J., Doerner, J. & Putterman, C. Neuropsychiatric lupus occurs independently of systemic autoimmunity. J. Immunol. 194, 2 (2015).

    Google Scholar 

  76. James, W. G., Hutchinson, P., Bullard, D. C. & Hickey, M. J. Cerebral leucocyte infiltration in lupus-prone MRL/MpJ-fas lpr mice — roles of intercellular adhesion molecule-1 and P-selectin. Clin. Exp. Immunol. 144, 299–308 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ma, X., Foster, J. & Sakic, B. Distribution and prevalence of leukocyte phenotypes in brains of lupus-prone mice. J. Neuroimmunol. 179, 26–36 (2006).

    CAS  PubMed  Google Scholar 

  78. Ballok, D. A., Ma, X., Denburg, J. A., Arsenault, L. & Sakic, B. Ibuprofen fails to prevent brain pathology in a model of neuropsychiatric lupus. J. Rheumatol. 33, 2199–2213 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Gelb, S., Stock, A. D., Anzi, S., Putterman, C. & Ben-Zvi, A. Mechanisms of neuropsychiatric lupus: the relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier. J. Autoimmun. 91, 34–44 (2018).

    PubMed  PubMed Central  Google Scholar 

  80. Stock, A. D., Gelb, S., Pasternak, O., Ben-Zvi, A. & Putterman, C. The blood brain barrier and neuropsychiatric lupus: new perspectives in light of advances in understanding the neuroimmune interface. Autoimmun. Rev. 16, 612–619 (2017).

    CAS  PubMed  Google Scholar 

  81. Schreiber, K. et al. Antiphospholipid syndrome. Nat. Rev. Dis. Primers 4, 18005 (2018).

    PubMed  Google Scholar 

  82. Gao, C. et al. Thrombotic role of blood and endothelial cells in uremia through phosphatidylserine exposure and microparticle release. PLOS ONE 10, e0142835b (2015).

    Google Scholar 

  83. Giannakopoulos, B. & Krilis, S. A. The pathogenesis of the antiphospholipid syndrome. N. Engl. J. Med. 368, 1033–1044 (2013).

    CAS  PubMed  Google Scholar 

  84. Narshi, C. B., Giles, I. P. & Rahman, A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 20, 5–13 (2011).

    CAS  PubMed  Google Scholar 

  85. Kittner, S. J. & Gorelick, P. B. Antiphospholipid antibodies and stroke: an epidemiological perspective. Stroke 23, I19–22 (1992).

    CAS  PubMed  Google Scholar 

  86. Andrade, R. M. et al. Seizures in patients with systemic lupus erythematosus: data from LUMINA, a multiethnic cohort (LUMINA LIV). Ann. Rheum. Dis. 67, 829–834 (2008).

    CAS  PubMed  Google Scholar 

  87. Appenzeller, S., Cendes, F. & Costallat, L. T. Epileptic seizures in systemic lupus erythematosus. Neurology 63, 1808–1812 (2004).

    PubMed  Google Scholar 

  88. McLaurin, E. Y., Holliday, S. L., Williams, P. & Brey, R. L. Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology 64, 297–303 (2005).

    CAS  PubMed  Google Scholar 

  89. Mok, M. Y. et al. Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus. J. Rheumatol. 32, 622–628 (2005).

    CAS  PubMed  Google Scholar 

  90. Sanna, G. et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J. Rheumatol. 30, 985–992 (2003).

    PubMed  Google Scholar 

  91. Tomietto, P. et al. General and specific factors associated with severity of cognitive impairment in systemic lupus erythematosus. Arthritis Rheum. 57, 1461–1472 (2007).

    CAS  PubMed  Google Scholar 

  92. Katzav, A. et al. Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice. J. Neuroimmunol. 272, 10–15 (2014).

    CAS  PubMed  Google Scholar 

  93. Chi, O. Z., Hunter, C., Liu, X. & Weiss, H. R. Effects of exogenous excitatory amino acid neurotransmitters on blood-brain barrier disruption in focal cerebral ischemia. Neurochem. Res. 34, 1249–1254 (2009).

    CAS  PubMed  Google Scholar 

  94. Du, H., Chen, M., Zhang, Y., Zhao, M. H. & Wang, H. Y. Cross-reaction of anti-DNA autoantibodies with membrane proteins of human glomerular mesangial cells in sera from patients with lupus nephritis. Clin. Exp. Immunol. 145, 21–27 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhao, Z. et al. Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential. Arthritis Rheum. 52, 522–530 (2005).

    CAS  PubMed  Google Scholar 

  96. 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, 1189–1193 (2001).

    CAS  PubMed  Google Scholar 

  97. Faust, T. W. et al. Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc. Natl Acad. Sci. USA 107, 18569–18574 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gao, H. X. et al. Depression is an early disease manifestation in lupus-prone MRL/lpr mice. J. Neuroimmunol. 207, 45–56 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Arinuma, Y., Yanagida, T. & Hirohata, S. Association of cerebrospinal fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 58, 1130–1135 (2008).

    CAS  PubMed  Google Scholar 

  100. Kozora, E. et al. Antibodies against N-methyl-D-aspartate receptors in patients with systemic lupus erythematosus without major neuropsychiatric syndromes. J. Neurol. Sci. 295, 87–91 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Petri, M. et al. Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus. J. Rheumatol. 37, 2032–2038 (2010).

    PubMed  Google Scholar 

  102. Brimberg, L. et al. Antibodies as mediators of brain pathology. Trends Immunol. 36, 709–724 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Husebye, E. S. et al. Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann. Rheum. Dis. 64, 1210–1213 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Nestor, J. et al. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J. Exp. Med. 215, 2554–2566 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Eber, T., Chapman, J. & Shoenfeld, Y. Anti-ribosomal P-protein and its role in psychiatric manifestations of systemic lupus erythematosus: myth or reality? Lupus 14, 571–575 (2005).

    CAS  PubMed  Google Scholar 

  106. Tzioufas, A. G. et al. The clinical relevance of antibodies to ribosomal-P common epitope in two targeted systemic lupus erythematosus populations: a large cohort of consecutive patients and patients with active central nervous system disease. Ann. Rheum. Dis. 59, 99–104 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Moscavitch, S. D., Szyper-Kravitz, M. & Shoenfeld, Y. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: the olfactory and immune system interrelationship. Clin. Immunol. 130, 235–243 (2009).

    CAS  PubMed  Google Scholar 

  108. Yoshio, T. et al. Quantification of antiribosomal P0 protein antibodies by ELISA with recombinant P0 fusion protein and their association with central nervous system disease in systemic lupus erythematosus. J. Rheumatol. 22, 1681–1687 (1995).

    CAS  PubMed  Google Scholar 

  109. Katzav, A. et al. Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system. Arthritis Rheum. 56, 938–948 (2007).

    CAS  PubMed  Google Scholar 

  110. Katzav, A. et al. Anti-P ribosomal antibodies induce defect in smell capability in a model of CNS-SLE (depression). J. Autoimmun. 31, 393–398 (2008).

    CAS  PubMed  Google Scholar 

  111. Perricone, C. et al. Smell and autoimmunity: a comprehensive review. Clin. Rev. Allergy Immunol. 45, 87–96 (2013).

    CAS  PubMed  Google Scholar 

  112. Song, C. & Leonard, B. E. The olfactory bulbectomised rat as a model of depression. Neurosci. Biobehav. Rev. 29, 627–647 (2005).

    PubMed  Google Scholar 

  113. Elkon, K. B., Parnassa, A. P. & Foster, C. L. Lupus autoantibodies target ribosomal P proteins. J. Exp. Med. 162, 459–471 (1985).

    CAS  PubMed  Google Scholar 

  114. Segovia-Miranda, F. et al. Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model. Arthritis Rheumatol. 67, 1598–1610 (2015).

    CAS  PubMed  Google Scholar 

  115. Nagai, T., Yanagida, T. & Hirohata, S. Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes. Mod. Rheumatol. 21, 57–62 (2011).

    CAS  PubMed  Google Scholar 

  116. 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, 473–477 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Dellavance, A. et al. Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases. Eur. J. Neurol. 19, 248–252 (2012).

    CAS  PubMed  Google Scholar 

  118. Verkman, A. S., Phuan, P. W., Asavapanumas, N. & Tradtrantip, L. Biology of AQP4 and anti-AQP4 antibody: therapeutic implications for NMO. Brain Pathol. 23, 684–695 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Waters, P. et al. Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch. Neurol. 65, 913–919 (2008).

    PubMed  Google Scholar 

  120. Waters, P. J. et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 78, 665–671 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Mader, S. et al. Understanding the antibody repertoire in neuropsychiatric systemic lupus erythematosus and neuromyelitis optica spectrum disorder: do they share common targets? Arthritis Rheumatol. 70, 277–286 (2018).

    CAS  PubMed  Google Scholar 

  122. Bradl, M. et al. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann. Neurol. 66, 630–643 (2009).

    CAS  PubMed  Google Scholar 

  123. Shimizu, F. et al. Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica. Sci. Transl. Med. 9, eaai9111 (2017).

    PubMed  PubMed Central  Google Scholar 

  124. Alexopoulos, H. et al. Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease. J. Neuroimmunol. 289, 8–11 (2015).

    CAS  PubMed  Google Scholar 

  125. Conti, F. et al. Autoantibody profile in systemic lupus erythematosus with psychiatric manifestations: a role for anti-endothelial-cell antibodies. Arthritis Res. Ther. 6, R366–R372 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Song, J., Park, Y. B., Lee, W. K., Lee, K. H. & Lee, S. K. Clinical associations of anti-endothelial cell antibodies in patients with systemic lupus erythematosus. Rheumatol. Int. 20, 1–7 (2000).

    CAS  PubMed  Google Scholar 

  127. Nara, H., Okamoto, H., Minota, S. & Yoshio, T. Mouse monoclonal anti-human thrombomodulin antibodies bind to and activate endothelial cells through NF-κB activation in vitro. Arthritis Rheum. 54, 1629–1637 (2006).

    CAS  PubMed  Google Scholar 

  128. Frampton, G. et al. Identification of candidate endothelial cell autoantigens in systemic lupus erythematosus using a molecular cloning strategy: a role for ribosomal P protein P0 as an endothelial cell autoantigen. Rheumatology (Oxford) 39, 1114–1120 (2000).

    CAS  Google Scholar 

  129. Williams, R. C. Jr., Sugiura, K. & Tan, E. M. Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 50, 1239–1247 (2004).

    CAS  PubMed  Google Scholar 

  130. Yamada, Y. et al. Antibodies to microtubule-associated protein-2 in the cerebrospinal fluid are a useful diagnostic biomarker for neuropsychiatric systemic lupus erythematosus. Mod. Rheum. 26, 562–568 (2016).

    CAS  Google Scholar 

  131. Matsui, T. et al. Identification of novel keratinocyte-secreted peptides dermokine-alpha/-beta and a new stratified epithelium-secreted protein gene complex on human chromosome 19q13.1. Genomics 84, 384–397 (2004).

    CAS  PubMed  Google Scholar 

  132. Park, G. T., Lim, S. E., Jang, S. I. & Morasso, M. I. Suprabasin, a novel epidermal differentiation marker and potential cornified envelope precursor. J. Biol. Chem. 277, 45195–45202 (2002).

    CAS  PubMed  Google Scholar 

  133. Ichinose, K. et al. Novel anti-suprabasin antibodies may contribute to the pathogenesis of neuropsychiatric systemic lupus erythematosus. Clin. Immunol. 193, 123–130 (2018).

    CAS  PubMed  Google Scholar 

  134. James, W. G., Bullard, D. C. & Hickey, M. J. Critical role of the alpha 4 integrin/VCAM-1 pathway in cerebral leukocyte trafficking in lupus-prone MRL/fas (lpr) mice. J. Immunol. 170, 520–527 (2003).

    CAS  PubMed  Google Scholar 

  135. Crispin, J. C. et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 181, 8761–8766 (2008).

    CAS  PubMed  Google Scholar 

  136. Shivakumar, S., Tsokos, G. C. & Datta, S. K. T cell receptor alpha/beta expressing double-negative (CD4–/CD8–) and CD4+T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J. Immunol. 143, 103–112 (1989).

    CAS  PubMed  Google Scholar 

  137. Jain, S., Stock, A., Macian, F. & Putterman, C. A distinct T follicular helper cell subset infiltrates the brain in murine neuropsychiatric lupus. Front. Immunol. 9, 487 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Crispin, J. C. et al. Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol. Med. 16, 47–57 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Chalmers, S. A. et al. Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. J. Autoimmun. 57, 42–52 (2015).

    CAS  PubMed  Google Scholar 

  140. Menke, J. et al. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice. J. Immunol. 181, 7367–7379 (2008).

    CAS  PubMed  Google Scholar 

  141. Crupi, R. et al. Reduced adult neurogenesis and altered emotional behaviors in autoimmune-prone B cell activating factor transgenic mice. Biol. Psychiatry 67, 558–566 (2010).

    CAS  PubMed  Google Scholar 

  142. Mondal, T. K., Saha, S. K., Miller, V. M., Seegal, R. F. & Lawrence, D. A. Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model. Brain Behav. Immun. 22, 949–959 (2008).

    CAS  PubMed  Google Scholar 

  143. Chalmers, S. A. et al. Highly selective inhibition of Bruton’s tyrosine kinase attenuates skin and brain disease in murine lupus. Arthritis Res. Ther. 20, 10 (2018).

    PubMed  PubMed Central  Google Scholar 

  144. Hanly, J. G., Walsh, N. M. & Sangalang, V. Brain pathology in systemic lupus erythematosus. J. Rheumatol. 19, 732–741 (1992).

    CAS  PubMed  Google Scholar 

  145. Duprez, T., Nzeusseu, A., Peeters, A. & Houssiau, F. A. Selective involvement of the choroid plexus on cerebral magnetic resonance images: a new radiological sign in patients with systemic lupus erythematosus with neurological symptoms. J. Rheumatol. 28, 387–391 (2001).

    CAS  PubMed  Google Scholar 

  146. Li, Y. et al. Behavioral deficits are accompanied by immunological and neurochemical changes in a mouse model for neuropsychiatric lupus (NP-SLE). Int. J. Mol. Sci. 16, 15150–15171 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Shiozawa, S., Kuroki, Y., Kim, M., Hirohata, S. & Ogino, T. Interferon-alpha in lupus psychosis. Arthritis Rheum. 35, 417–422 (1992).

    CAS  PubMed  Google Scholar 

  148. Fragoso-Loyo, H., Atisha-Fregoso, Y., Llorente, L. & Sanchez-Guerrero, J. Inflammatory profile in cerebrospinal fluid of patients with headache as a manifestation of neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 52, 2218–2222 (2013).

    CAS  Google Scholar 

  149. 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, 1192–1201 (2009).

    CAS  PubMed  Google Scholar 

  150. Ronnblom, L., Alm, G. V. & Eloranta, M. L. Type I interferon and lupus. Curr. Opin. Rheumatol. 21, 471–477 (2009).

    PubMed  Google Scholar 

  151. Karageorgas, T. P., Tseronis, D. D. & Mavragani, C. P. Activation of type I interferon pathway in systemic lupus erythematosus: association with distinct clinical phenotypes. J. Biomed. Biotechnol. 2011, 273907 (2011).

    PubMed  PubMed Central  Google Scholar 

  152. Yoshio, T. et al. IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus 25, 997–1003 (2016).

    CAS  PubMed  Google Scholar 

  153. Fragoso-Loyo, H., Atisha-Fregoso, Y., Nunez-Alvarez, C. A., Llorente, L. & Sanchez-Guerrero, J. Utility of interferon-alpha as a biomarker in central neuropsychiatric involvement in systemic lupus erythematosus. J. Rheumatol 39, 504–509 (2012).

    CAS  PubMed  Google Scholar 

  154. Wen, J. et al. Inhibiting TWEAK (TNF-like weak inducer of apoptosis) signaling ameliorates blood brain barrier integrity and neuronal damage in neuropsychiatric lupus prone MRL/lpr mice. J. Immunol. 192, 1 (2014).

    Google Scholar 

  155. Wen, J. et al. Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway. J. Autoimmun. 43, 44–54 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fragoso-Loyo, H., Atisha-Fregoso, Y., Nunez-Alvarez, C. A. & Llorente, L. Utility of TWEAK to assess neuropsychiatric disease activity in systemic lupus erythematosus. Lupus 25, 364–369 (2016).

    CAS  PubMed  Google Scholar 

  157. Katsumata, Y. et al. Diagnostic reliability of cerebral spinal fluid tests for acute confusional state (delirium) in patients with systemic lupus erythematosus: interleukin 6 (IL-6), IL-8, interferon-alpha, IgG index, and Q-albumin. J. Rheumatol. 34, 2010–2017 (2007).

    CAS  PubMed  Google Scholar 

  158. Hirohata, S. et al. Accuracy of cerebrospinal fluid IL-6 testing for diagnosis of lupus psychosis. A multicenter retrospective study. Clin. Rheumatol. 28, 1319–1323 (2009).

    PubMed  Google Scholar 

  159. Asano, T. et al. Evaluation of blood-brain barrier function by quotient alpha2 macroglobulin and its relationship with interleukin-6 and complement component 3 levels in neuropsychiatric systemic lupus erythematosus. PLOS ONE 12, e0186414 (2017).

    PubMed  PubMed Central  Google Scholar 

  160. Ichinose, K. et al. Distinguishing the cerebrospinal fluid cytokine profile in neuropsychiatric systemic lupus erythematosus from other autoimmune neurological diseases. Clin. Immunol. 157, 114–120 (2015).

    CAS  PubMed  Google Scholar 

  161. Wang, J. B. et al. Role of IL-1β, IL-6, IL-8 and IFN-γ in pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous. Int. J. Clin. Exp. Med. 8, 16658–16663 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Gilkeson, G. S. Complement-targeted therapies in lupus. Curr. Treatm Opt. Rheumatol. 1, 10–18 (2015).

    Google Scholar 

  164. Alexander, J. J., Jacob, A., Bao, L., Macdonald, R. L. & Quigg, R. J. Complement-dependent apoptosis and inflammatory gene changes in murine lupus cerebritis. J. Immunol. 175, 8312–8319 (2005).

    CAS  PubMed  Google Scholar 

  165. Jongen, P. J., Boerbooms, A. M., Lamers, K. J., Raes, B. C. & Vierwinden, G. Diffuse CNS involvement in systemic lupus erythematosus: intrathecal synthesis of the 4th component of complement. Neurology 40, 1593–1596 (1990).

    CAS  PubMed  Google Scholar 

  166. Jongen, P. J. et al. Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system. Acta Neurol. Scand. 101, 116–121 (2000).

    CAS  PubMed  Google Scholar 

  167. Sakuma, Y., Nagai, T., Yoshio, T. & Hirohata, S. Differential activation mechanisms of serum C5a in lupus nephritis and neuropsychiatric systemic lupus erythematosus. Mod. Rheumatol. 27, 292–297 (2017).

    CAS  PubMed  Google Scholar 

  168. Dobrowolski, C. & Erkan, D. Treatment of antiphospholipid syndrome beyond anticoagulation. Clin. Immunol. https://doi.org/10.1016/j.clim.2018.03.001 (2018).

    Article  PubMed  Google Scholar 

  169. Kronbichler, A. et al. Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syndrome: a case report. Medicine 93, e143 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Shapira, I., Andrade, D., Allen, S. L. & Salmon, J. E. Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum. 64, 2719–2723 (2012).

    CAS  PubMed  Google Scholar 

  171. Paul, F., Murphy, O., Pardo, S. & Levy, M. Investigational drugs in development to prevent neuromyelitis optica relapses. Expert Opin. Investig. Drugs 27, 265–271 (2018).

    CAS  PubMed  Google Scholar 

  172. Lei, H. W. et al. Neuropsychiatric involvement in lupus is associated with the Nogo-a/NgR1 pathway. J. Neuroimmunol. 311, 22–28 (2017).

    CAS  PubMed  Google Scholar 

  173. Wendeln, A. C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Schrepf, A. et al. A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis. Nat. Commun. 9, 2243 (2018).

    PubMed  PubMed Central  Google Scholar 

  175. Nystedt, J. et al. Altered white matter microstructure in lupus patients: a diffusion tensor imaging study. Arthritis Res. Ther. 20, 21 (2018).

    PubMed  PubMed Central  Google Scholar 

  176. Ceccarelli, F. et al. Genetic factors in systemic lupus erythematosus: contribution to disease phenotype. J. Immunol. Res. 2015, 745647 (2015).

    PubMed  PubMed Central  Google Scholar 

  177. de Vries, B. et al. TREX1 gene variant in neuropsychiatric systemic lupus erythematosus. Ann. Rheum. Dis. 69, 1886–1887 (2010).

    PubMed  Google Scholar 

  178. Namjou, B. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 12, 270–279 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Lundstrom, E. et al. HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus. Ann. Rheum. Dis. 72, 1018–1025 (2013).

    PubMed  Google Scholar 

  180. Rullo, O. J. & Tsao, B. P. Recent insights into the genetic basis of systemic lupus erythematosus. Ann. Rheum. Dis. 72 (Suppl. 2), ii56–ii61 (2013).

    CAS  PubMed  Google Scholar 

  181. Koga, M. et al. Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population. J. Hum. Gen. 56, 503–507 (2011).

    CAS  Google Scholar 

  182. 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, 620–625 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 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, 59–62 (2003).

    CAS  PubMed  Google Scholar 

  184. Tokunaga, M. et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann. Rheum. Dis. 66, 470–475 (2007).

    CAS  PubMed  Google Scholar 

  185. Dale, R. C. et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 83, 142–150 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Jacob, A. et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch. Neurol. 65, 1443–1448 (2008).

    PubMed  Google Scholar 

  187. Pranzatelli, M. R. et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J. Pediatr. Hematol. Oncol. 28, 585–593 (2006).

    CAS  PubMed  Google Scholar 

  188. Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Manzi, S. et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann. Rheum. Dis. 71, 1833–1838 (2012).

    CAS  PubMed  Google Scholar 

  190. Hanly, J. G. in Systemic Lupus Erythematosus 5th edn (ed. Lahita, R. G.) 727–746 (Elsevier, 2005).

  191. Erkan, D., Salmon, J. & Lockshin, M. in Kelley and Firestein’s Textbook of Rheumatology (ed. Firestein, G. S.) 1389–1399 (Elsevier, 2017).

  192. 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, 2870–2878 (2001).

    CAS  PubMed  Google Scholar 

  193. Jung, H. et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 62, 863–868 (2010).

    CAS  PubMed  Google Scholar 

  194. Cervera, R. CAPS Registry. Lupus 21, 755–757 (2012).

    CAS  PubMed  Google Scholar 

  195. Furie, R. et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).

    CAS  PubMed  Google Scholar 

  197. Chalmers, S. A. et al. CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin. Immunol. 185, 100–108 (2017).

    CAS  PubMed  Google Scholar 

  198. Hendriks, R. W. Drug discovery: new Btk inhibitor holds promise. Nat. Chem. Biol. 7, 4–5 (2011).

    CAS  PubMed  Google Scholar 

  199. Jongstra-Bilen, J. et al. Dual functions of Bruton’s tyrosine kinase and Tec kinase during Fcγ receptor-induced signaling and phagocytosis. J. Immunol. 181, 288–298 (2008).

    CAS  PubMed  Google Scholar 

  200. Ni Gabhann, J. et al. Btk regulates macrophage polarization in response to lipopolysaccharide. PLOS ONE 9, e85834 (2014).

    PubMed  PubMed Central  Google Scholar 

  201. Chalmers, S. A. et al. Therapeutic blockade of immune complex-mediated glomerulonephritis by highly selective inhibition of Bruton’s tyrosine kinase. Sci. Rep. 6, 26164 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Mina-Osorio, P. et al. Suppression of glomerulonephritis in lupus-prone NZB × NZW mice by RN486, a selective inhibitor of Bruton’s tyrosine kinase. Arthritis Rheum. 65, 2380–2391 (2013).

    CAS  PubMed  Google Scholar 

  203. Rankin, A. L. et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J. Immunol. 191, 4540–4550 (2013).

    CAS  PubMed  Google Scholar 

  204. Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Zardi, E. M., Taccone, A., Marigliano, B., Margiotta, D. P. & Afeltra, A. Neuropsychiatric systemic lupus erythematosus: tools for the diagnosis. Autoimmun. Rev. 13, 831–839 (2014).

    PubMed  Google Scholar 

  206. Kivity, S., Agmon-Levin, N., Zandman-Goddard, G., Chapman, J. & Shoenfeld, Y. Neuropsychiatric lupus: a mosaic of clinical presentations. BMC Med. 13, 43 (2015).

    PubMed  PubMed Central  Google Scholar 

  207. Zhang, L., Fu, T., Yin, R., Zhang, Q. & Shen, B. Prevalence of depression and anxiety in systemic lupus erythematosus: a systematic review and meta-analysis. BMC Psychiatry 17, 70 (2017).

    PubMed  PubMed Central  Google Scholar 

  208. Torreggiani, S. et al. Chorea, a little-known manifestation in systemic lupus erythematosus: short literature review and four case reports. Pediatr. Rheumatol. 11, 36 (2013).

    Google Scholar 

  209. Li, X. Y., Xiao, H. B. & Pai, P. Myelitis in systemic lupus erythematosus. J. Clin. Neurosci. 44, 18–22 (2017).

    PubMed  Google Scholar 

  210. Piga, M. et al. Demyelinating syndrome in SLE encompasses different subtypes: do we need new classification criteria? Pooled results from systematic literature review and monocentric cohort analysis. Autoimmun. Rev. 16, 244–252 (2017).

    PubMed  Google Scholar 

  211. Fragoso-Loyo, H. et al. Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus. Arthritis Rheum. 56, 1242–1250 (2007).

    CAS  PubMed  Google Scholar 

  212. Dellalibera-Joviliano, R., Dos Reis, M. L., Cunha Fde, Q. & Donadi, E. A. Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus. J. Rheumatol. 30, 485–492 (2003).

    CAS  PubMed  Google Scholar 

  213. Baraczka, K., Nekam, K., Pozsonyi, T., Szuts, I. & Ormos, G. Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus. Eur. J. Neurol. 11, 37–42 (2004).

    CAS  PubMed  Google Scholar 

  214. Quaresma, M. V. et al. Anti-TNF-α and hydralazine drug-induced lupus. An. Bras. Dermatol. 90, 125–129 (2015).

    PubMed  PubMed Central  Google Scholar 

  215. Groom, J. R. et al. BAFF and MyD88 signals promote a lupus like disease independent of T cells. J. Exp. Med. 204, 1959–1971 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Zhang, J. et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J. Immunol. 166, 6–10 (2001).

    CAS  PubMed  Google Scholar 

  217. Crow, M. K. Type I interferon in the pathogenesis of lupus. J. Immunol. 192, 5459–5468 (2014).

    CAS  PubMed  Google Scholar 

  218. Baechler, E. C., Gregersen, P. K. & Behrens, T. W. The emerging role of interferon in human systemic lupus erythematosus. Curr. Opin. Immunol. 16, 801–807 (2004).

    CAS  PubMed  Google Scholar 

  219. Wichers, M. & Maes, M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int. J. Neuropsychopharmacol. 5, 375–388 (2002).

    CAS  PubMed  Google Scholar 

  220. Stock, A. D., Wen, J. & Putterman, C. Neuropsychiatric lupus, the blood brain barrier, and the TWEAK/Fn14 pathway. Front. Immunol. 4, 484 (2013).

    PubMed  PubMed Central  Google Scholar 

  221. Ronnblom, L. & Elkon, K. B. Cytokines as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 339–347 (2010).

    PubMed  Google Scholar 

Download references

Acknowledgements

N.S. was supported by the Hospital for Special Surgery Research Institute Rheumatology Training Program grant (T32 AR071302). A.D.S. was supported by the Albert Einstein College of Medicine Medical Scientist Training grant (T32-GM007822). C.P. was supported by an R01 grant from the US National Institute of Arthritis and Musculoskeletal Diseases (AR065594).

Reviewer information

Nature Reviews Rheumatology thanks S. Hirohata and the other anonymous reviewers, for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Noa Schwartz, Ariel D. Stock.

Authors and Affiliations

  1. Division of Rheumatology, Hospital for Special Surgery, New York, NY, USA

    Noa Schwartz

  2. Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

    Ariel D. Stock & Chaim Putterman

  3. Division of Rheumatology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA

    Chaim Putterman

Authors
  1. Noa Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ariel D. Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chaim Putterman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article and contributed to discussions of its content as well as the writing and review or editing of the manuscript before submission.

Corresponding author

Correspondence to Chaim Putterman.

Ethics declarations

Competing interests

C.P. declares that he has received research funding from Biogen Idec for studies of the TNF-like weak inducer of apoptosis (TWEAK) pathway and from Boehringer Ingelheim for studies of tyrosine-protein kinase BTK inhibition in animal models of lupus. N.S. and A.D.S. declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwartz, N., Stock, A.D. & Putterman, C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol 15, 137–152 (2019). https://doi.org/10.1038/s41584-018-0156-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-018-0156-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing