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Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers

Nature Reviews Neurology volume 10, pages 579–596 (2014)Cite this article

Subjects

Key Points

  • Neuropsychiatric symptoms can be an important complication of systemic lupus erythematosus (SLE); among patients with neuropsychiatric SLE (NPSLE), neuropsychiatric manifestations contribute considerably to morbidity and mortality

  • Clinical manifestations of NPSLE are wide-ranging, and can involve the CNS and PNS; thus, no single diagnostic test for NPSLE exists, and diagnosis remains mainly an exercise of exclusion

  • Both the profile and severity of neuropsychiatric impairment in patients with NPSLE fluctuate over time, independently of disease activity

  • Disruption of blood–brain barrier integrity, which enables diffusion of small molecules and cytokines into the cerebrospinal fluid, is considered a pivotal component of NPSLE development

  • Consensus case-definition criteria for NPSLE-associated central and peripheral neurological syndromes represent an important development that has improved the diagnosis and management of NPSLE; however, some manifestations are still misdiagnosed

  • The rationale for understanding the pathophysiology of NPSLE is the potential to develop biomarkers and selective therapies targeting the identified pathogenetic processes, thereby ultimately improving the management of the disease

Abstract

Systemic lupus erythematosus (SLE) is a complex clinical syndrome, elements of which remain poorly understood. Although recognized over 140 years ago when Kaposi recorded the systemic nature and manifestations of the disease, CNS involvement represents one of the least understood aspects of SLE. This knowledge gap remains despite the fact that up to 75% of adults and children with SLE will, at some point over the course of the disease and to different extents, experience the various disabling effects of neuropsychiatric SLE (NPSLE). Indeed, after decades of research, our understanding of the underlying pathophysiology of NPSLE, in particular, remains limited. Numerous factors contribute to the immune dysfunction that occurs in SLE, including genetic, environmental and hormonal influences, and the contributory or predisposing components that lead to neurological tropism of disease in some patients have not been clearly demonstrated. Features of NPSLE pathogenesis that might be directly linked to clinical manifestations have been identified; however, the complexity and variety of NPSLE symptoms and the clinical overlap with other psychiatric disorders continue to make accurate diagnosis difficult and time-consuming. Thus, efforts to define biomarkers of NPSLE are needed to improve prediction of disease outcomes and guide treatment. In this article, we review the manifestation and pathogenesis of NPSLE, focusing on the features that might aid identification of potential biomarkers.

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Figure 1: SLE-associated neurological features.
Figure 2: Rational approach to evaluation and differential diagnosis of NPSLE.
Figure 3: Potential pathogenic mechanisms in NPSLE.
Figure 4: Immune response to molecules related to cell stress and repair in NPSLE.

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Acknowledgements

We gratefully acknowledge Marinos C. Dalakas (University of Athens Medical School, Athens, Greece) as well as Jean-Louis Pasquali (Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France) and Vincent Fontaa (Centre Hospitalier Universitaire de Strasbourg, Pôle Psychiatrie, Strasbourg, France) for their critical reading of this manuscript. We thank Ralph C. Williams Jr (University of New Mexico School of Medicine, Albuquerque, NM, USA) and Jean Sibilia (Centre Hospitalier Universitaire de Strasbourg, Hôpital de Hautepierre, Service de rhumatologie, Strasbourg, France) for providing serum samples from patients with SLE and healthy donors, respectively, Rufus Burlingame (Inova Diagnostics Inc., San Diego, CA, USA) for providing chromatin-coated ELISA plates, and Maria Kotovskaya for performing ELISA tests that produced the data summarized in Figure 4. We thank Athanasios G. Tzioufas (University of Athens Medical School, Athens, Greece) for providing the MRI scans shown in Figure 1. Research in the laboratory of S.M. is supported financially by the French Centre National de la Recherche Scientifique (CNRS), Région Alsace, and the Laboratory of Excellence Medalis (ANR-10-LABX-0034), Initiative of Excellence (IdEx), Strasbourg University, France.

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    Hélène Jeltsch-David & Sylviane Muller

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S.M. is a consultant for ImmuPharma. H.J. D. declares no competing interests.

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Jeltsch-David, H., Muller, S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol 10, 579–596 (2014). https://doi.org/10.1038/nrneurol.2014.148

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