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.
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.
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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).
Nature Reviews Rheumatology thanks S. Hirohata and the other anonymous reviewers, for their contribution to the peer review of this work.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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
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