Immunological Medicine

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Diversity of neuropsychiatric manifestations in

systemic lupus erythematosus

Yuichiro Fujieda

To cite this article: Yuichiro Fujieda (2020) Diversity of neuropsychiatric manifestations

in systemic lupus erythematosus, Immunological Medicine, 43:4, 135-141, DOI:
10.1080/25785826.2020.1770947

To link to this article: https://doi.org/10.1080/25785826.2020.1770947

© 2020 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group on behalf of the Japanese Society of
Clinical Immunology.

Published online: 27 May 2020.

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IMMUNOLOGICAL MEDICINE
2020, VOL. 43, NO. 4, 135–141
https://doi.org/10.1080/25785826.2020.1770947

REVIEW ARTICLE

Diversity of neuropsychiatric manifestations in systemic lupus

erythematosus
Yuichiro Fujieda
Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido
University, Sapporo, Japan

ABSTRACT ARTICLE HISTORY

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by Received 19 March 2020
diverse organ damages resulting from various autoantibodies, such as antinuclear or anti- Accepted 10 May 2020
DNA antibodies. Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric
KEYWORDS
disorders complicated with SLE and can be challenging for physicians to manage. NPSLE has
Systemic lupus
a broad spectrum and high heterogeneity of clinical phenotypes, including headaches, psy- erythematosus; neuro-
chiatric symptoms and peripheral neuropathy. Additionally, various immune effectors have psychiatric lupus; post-
been reported to contribute to the pathogenesis, including cytokines, cell-mediated inflam- steroid neuropsychiatric
mation and brain-reactive autoantibodies. In some patients with SLE, neuropsychiatric symp- manifestation; antibodies
toms develop for the first time after the initiation of the steroid treatment, hindering the against subunits of the N-
differentiation from steroid psychosis. The administration of high doses of steroids in methyl-D-aspartate receptor
patients with SLE is believed to trigger psychiatric symptoms. No clear evidence has yet
been found regarding the treatment of NPSLE. Therefore, NPSLE-specific markers need to be
developed, and treatment guidelines should be established. This article provides an overview
of NPSLE as well as its pathogenesis and treatment.

1. Introduction 2. Classification of NPSLE

Systemic lupus erythematosus (SLE) is a systemic
autoimmune disease characterised by the production
of various autoantibodies, such as antinuclear or
anti-DNA antibodies [1]. The management of the
neuropsychiatric manifestation of SLE (NPSLE) is
especially challenging. NPSLE has diverse and highly
heterogeneous clinical phenotypes, including head-
aches, psychiatric symptoms and peripheral neur-
opathy. In addition, many other SLE complications,
such as infections of the central nervous system
(CNS), drug-induced diseases and metabolic disor-
ders, cause neuropsychiatric symptoms. Various
immune effectors, including brain-reactive autoanti-
bodies, cytokines and cell-mediated inflammation
have been reported as the contributors of SLE
pathogenesis. However, patients with NPSLE are
often weakly responsive to immunosuppressive ther-
apy. Therefore, NPSLE-specific markers need to be
developed, and specific treatment guidelines should
be established. This review article describes the clin-
ical features, pathogenic mechanisms and manage-
ment of patients with NPSLE.
NPSLE refers to neurological and psychiatric disor-
ders complicated with SLE. The symptoms of
NPSLE have been classified into 19 neuropsychiatric
(NP) manifestations by the American College of
Rheumatology (ACR) [2], leading to the elucidation
of the incidence and features of the disease through
clinical studies. The defined 19 NP manifestations
comprised of two major classifications such as CNS
and peripheral nervous system. CNS manifestations
are further divided into ‘focal’ and ‘diffuse’
(Table 1). The prevalence of NPSLE in patients with
SLE is 30–40%. Additionally, 50–60% of these
develop NPSLE within one year of the SLE onset
[3]. The prevalence of each type of NPSLE signifi-
cantly differs according to the study design followed.
These discrepancies might be due to the ambiguity
in the diagnosis of NP symptoms, especially of those
non-specific to SLE, such as headache or mood dis-
orders. Cerebrovascular disorders and epileptic seiz-
ures are found in 5–15% of patients with NPSLE.
Cognitive impairment, mood disorders, acute confu-
sional state or peripheral neuropathy are found in
only 1–5% patients, whereas psychosis, myelitis,
involuntary movements of the limbs and facial

CONTACT Yuichiro Fujieda edaichi@med.hokudai.ac.jp Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine
and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 8, Kita-ku, Sapporo 060-8648, Japan
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Japanese Society of Clinical Immunology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
136 Y. FUJIEDA

Table 1. Neuropsychiatric manifestations in systemic lupus erythematosus.

Central nervous system (CNS) Peripheral nervous system (PNS)
Diffuse manifestations Acute confusional state –
Anxiety disorder
Cognitive dysfunction
Mood disorders
Psychosis
Focal manifestations Aseptic meningitis Guillain-Barre syndrome
Cerebrovascular disease Autonomic disorder
Demyelinating syndrome Mononeuropathy, single/multiplex
Headache Myasthenia gravis
Movement disorder Neuropathy, cranial
Myelopathy Plexopathy
Seizures Polyneuropathy
Adapted from the guidelines to define neuropsychiatric nomenclature by the by the American College of Rheumatology
in 1999 [2].

muscles, and aseptic meningitis are extremely rare.
In Systemic Lupus International Collaborating
Clinic Criteria (SLICC) [4] proposed in 2012 for the
classification of SLE, epileptic seizures, psychosis,
mononeuritis multiplex, myelitis, peripheral neur-
opathy, cranial nerve disorders and acute confu-
sional state are defined as the NP manifestations of
SLE, whereas other types of NP symptoms, such as
headaches, mood disorders and cerebrovascular dis-
orders are excluded due to their low specificity. In
2019, new classification criteria for SLE were pro-
posed by the European League Against Rheumatism
(EULAR)/American College of Rheumatology
(ACR) [5,6]. In the new criteria, only delirium,
psychosis and seizure are defined as the NP mani-
festations to improve specificity for diagnosis with
SLE. Diagnosis with the new criteria will be sub-
jected to verification with time.
3. Autoantibodies and NPSLE
SLE is characterised by multiple types of autoanti-
bodies with multi-organ involvement. Several anti-
bodies identified in patients with NPSLE are
believed to contribute to the pathogenesis of the dis-
eases, and various manifestations of NPSLE are now
explained according to the antibodies present. Most
cerebrovascular disorders in NPSLE are due to anti-
phospholipid antibodies (aPL) associated with the
development of thrombosis. In addition, aPL has
been reported to be associated with headaches, cho-
rea, transverse myelitis and epileptic seizures [7,8].
Previous reports have shown that the anti-ribosomal
protein P antibody is associated with psychiatric
symptoms [9,10]. Additionally, the antibodies
against the subunits of the N-methyl-D-aspartate
(NMDA) receptor (anti-DNA/NR2 antibodies) are
associated with diffuse NPSLE [11,12]. Increased
levels of anti-DNA/NR2 antibodies in the spinal
fluid are triggered by a failure of the blood–brain
barrier (BBB) and can predict a recurrence of
NPSLE. A systematic review of the association
between NPSLE and autoantibodies has previously
been reported. It shows that only aPL is associated
with the onset of NPSLE and that there is no correl-
ation with other antibodies [13]. However, since the
symptoms of NPSLE vary and overlap, the possible
roles of other autoantibodies cannot be excluded.
4. Autoantibodies and the mechanism
of NPSLE
The graphical summary was provided regarding
autoantibodies and mechanism of NPSLE (Figure 1).
Anti-DNA/NR2 and anti-ribosomal P antibodies are
considered to target specific parenchymal structures
in the brain and underly the onset of NP manifesta-
tions. Anti-Sm antibodies (anti-Sm) and anti-U1-
ribonucleoprotein antibodies (anti-RNP) are fre-
quently found in patients with NPSLE. In addition,
anti-aquaporin 4 antibodies (anti-AQP4) which are
diagnostic marker for neuromyelitis optica spectrum
disorder (NMOSD) are contribute to NPSLE.
4.1. Anti-DNA/NR2 antibodies
Anti-DNA/NR2 antibodies are a subset of anti-DNA
antibodies that cross-reacts with the GluN2(NR2)
subunit of the NMDA receptor (NMDAR). NMDA
receptor-mediated excitotoxicity has been reported
to induce neuronal cell death [14]. NMDAR is one
of the ionotropic receptors of glutamate, an excita-
tory neurotransmitter in the nervous system, and
plays a central role in learning and memory.
NMDAR is a tetramer expressed on the cell mem-
brane and composed of GluN1 (NR1) and GluN2
(NR2) subunits. Anti-DNA/NR2 antibodies bind to
NR2, assemble the channel and induce cell death by
a high influx of calcium into the cell [15]. Notably,
anti-DNA/NR2 antibodies differ from other anti-
NMDAR antibodies found in patients who have
ovarian teratoma. The anti-NMDAR antibodies are
targeted against NR1 leading to the endocytosis of
NMDAR [16]. Although anti-DNA/NR2 antibodies
have been detected in a mouse model immunized
with the peptide antigens [14], the phenotype could
 IMMUNOLOGICAL MEDICINE 137

Figure 1. Autoantibodies and the mechanism of neuropsychiatric systemic lupus erythematosus. Anti-DNA/NR2 and anti-ribo-
somal P antibodies (anti-ribosomal P) are considered to target specific parenchymal structures in the brain and underly the
onset of NP manifestations. Anti-Sm antibodies (anti-Sm), anti-U1-ribonucleoprotein antibodies (anti-RNP) and anti-ribosomal P
enhance the production of inflammatory cytokines in human monocytes. Anti-aquaporin 4 antibodies (anti-AQP4) which are
diagnostic marker for neuromyelitis optica spectrum disorder are contribute to NPSLE. Anti-DNA/NR2: the antibodies against
the subunits of the N-methyl-D-aspartate (NMDA) receptor.

not be determined. In this model, a breach in the
integrity of the BBB is required for the antibodies to
access the brain tissue and affect the neuronal func-
tion and viability. Lipopolysaccharide (LPS) injec-
tion as a surrogate for infection causes antibody
influx into the hippocampus, and epinephrine injec-
tion as a surrogate for stress allows the antibody to
penetrate the amygdala. In a previous study that
used LPS, hippocampal neurons decreased in num-
ber, and the mice experienced memory loss [17]. In
another study, which used epinephrine, the neurons
in the amygdala decreased in number, and the mice
displayed increased anxiety [18]. These findings sug-
gest that the regional disruption of the BBB depends
on the agents used to modify the BBB and the same
antibody can cause diverse behavioural changes.
BBB breach causes antibody flow into the brain
with a peak influx 48 h after the breach and dis-
appear from the brain in two weeks. The evaluation
of the nerve damage using 18F-fluorodeoxyglucose
positron emission tomography in mice showed low
glucose uptake in the brain two weeks after the BBB
breach [19]. At 4 weeks post-BBB breach, the mice
exhibit increased glucose uptake in the affected
region. Interestingly, although metabolism returned
to normal, the numbers of neurons and dendritic
spines, as well as dendritic complexity sustained to
decrease after 8 weeks [20]. The mice also exhibit
behavioural disorders from 8 weeks after subjected
to an anti-DNA/NR2 antibody-mediated insult.
Taken together, the anti-DNA/NR2 antibody-
induced brain pathology proceeds through an acute
phase of excitotoxic neuronal loss, followed by per-
manent alteration in neuronal integrity and by spa-
tial memory impairment. However, these findings
are found in only experimental mice. Since some
NPSLE patients with severe diffuse symptoms recov-
ered completely after treatment, further research is
needed to clarify the mechanism in human.
Arinuma et al. [21] have revealed the mechanism of
long-term neuronal dysfunction and shown that
activated microglia and C1q are critical mediators of
the neuronal damage. The involvement of microglia
and complements is a possible explanation for the
changes occurring during both the acute and
chronic phases [21,22]. They have also shown that
angiotensin-converting enzyme (ACE) inhibitor can
prevent the microglia activation and preserve neur-
onal function and cognitive performance.
Accordingly, ACE inhibitors may be a promising
class of therapeutics against the cognitive impair-
ment in SLE.
4.2. Anti-ribosomal P protein antibodies
Ribosomes are organelles of protein synthesis and
are composed of ribosomal protein–RNA complexes.
Ribosomal P protein refers to three types of phos-
phorylated proteins present on the 60S subunit of
eukaryotic ribosomes. It is also known as the neur-
onal surface P antigen (NSPA) due to their expres-
sion on the neuronal cell surface in the cerebral
cortex, hippocampus and amygdala [23]. P antigen
consists of the highly conserved carboxy-terminal
138 Y. FUJIEDA
residues of three ribosomal phosphoproteins, P0
(38 kDa), P1 (19 kDa) and P2 (17 kDa) [24]. Anti-
ribosomal P protein antibodies recognize all these
proteins [25], increase cellular calcium influx and
induce cell death [26]. Passive transfer experiments
in mice have shown that anti-ribosomal P protein
antibodies isolated from SLE patients induce olfac-
tory abnormalities [27], depression-like manifesta-
tions [28] and memory impairment [29]. In
addition, ribosomal P proteins are expressed on the
surfaces of peripheral blood monocytes. Binding of
anti-ribosomal P protein antibody to monocytes
increases the production of proinflammatory cyto-
kines, such as tumour necrosis factor-a and interleu-
kin (IL)-6 from monocytes [30]. Since these
cytokines contribute to the BBB breach, the associ-
ation between anti-ribosomal P antibodies and BBB
breach has recently been considered.
4.3. Anti-Sm antibodies and anti-U1-
ribonucleoprotein antibodies
Anti-Sm recognize the U1, U2, U4/U6 and U5 small
nuclear RNPs (snRNPs), and anti-RNP recognize
the U1snRNPs, respectively [31]. The presence of
serum anti-Sm correlates with the prevalence of dif-
fuse NPSLE [32], and high mortality in patients
with NPSLE [33]. High anti-RNP levels were also
found in patients with NPSLE in both serum and
cerebrospinal fluid [34]. Matsueda et al. showed that
anti-Sm and anti-RNP bind on the cell surface of
human monocyte. In addition, anti-Sm and anti-
RNP synergistically enhance the production of IL-6
by human monocytes [35]. Since anti-Sm and anti-
RNP often coexist, the synergistic effects by the two
antibodies may explain the mechanism of the BBB
breach in patients with NPSLE.
4.4. Anti-aquaporin 4 antibodies
NMOSD is an autoimmune disease characterised by
damage to CNS, and the presence of anti-AQP4
[36]. NMOSD commonly affects areas with high lev-
els of AQP-4 expression, such as demyelinating spi-
nal cord lesions and/or optic neuritis.
Demyelination is also part of the symptoms in
NPSLE. Since it was unclear whether the autoanti-
bodies found in NPSLE with demyelinating symp-
toms are common to those in NMOSD, Mader et al.
clarified the prevalence of anti-AQP4 in patients
with NPSLE [37]. Anti-AQP4 was found in 27% of
NPSLE with demyelinating symptoms. Notably,
NPSLE without demyelinating symptoms was nega-
tive of anti-AQP4, suggesting that anti-AQP4 may
be associated with demyelination in NPSLE.
5. Cytokines in the cerebrospinal fluid (CSF)
Previous reports showed elevated levels of several
cytokines, such as fractalkine [38], IL-6 [39,40], IL-8
[41], interferon-a (IFN-a) [42,43], IL-1, BAFF (B
cell-activating factor) and APRIL (a proliferation-
inducing ligand) [44] in the CSF of patients with
NPSLE. Hirohata et al. showed that the presentation
of high IL-6 levels in the CSF was the most sensitive
and abnormal laboratory test results in NPSLE [45].
Santer et al. showed that the CSF from SLE patients
contains abnormally high levels of IFN-a-inducing
activity. In the CSF, immune complexes bound to
FCcRII on plasmacytoid dendritic cells leading to
cytokine production via TLR7 activation [42].
Therefore, autoantibodies entering the brain and
reacting with neurons and glial cells may increase
the levels of cytokines in the CSF.
6. Post-steroid NP manifestation in SLE
In some patients with SLE, NP symptoms develop
for the first time after the initiation of the steroid
treatment, hindering the differentiation from steroid
psychosis. Interestingly, the incidence of ‘post-ster-
oid NP manifestation’ (PSNP) is significantly higher
in patients with SLE than in those with other auto-
immune diseases. To clarify the characteristics of
PSNP in SLE, we defined the NP symptoms that
occur after the steroid administration as PSNP-SLE,
and the NPSLE with NP symptoms that develop
before high-dose steroid treatments as ‘de novo
NPSLE’ [46]. Subsequently, we compared the char-
acteristics including the complications of the APS
and previous medical history of psychiatric disor-
ders in PSNP-SLE and de novo NPSLE and revealed
the risk factors for PSNP-SLE. Most of the PSNP-
SLE cases show diffuse manifestations, whereas de
novo NPSLE shows focal manifestation according to
the ACR classification. Further, we have evaluated
the clinical significance of anti-DNA/NR2 antibodies
in both de novo NSPLE and PSNP-SLE [47]. Anti-
DNA/NR2 antibody levels in PSNP-SLE are similar
with the levels in de novo NPSLE, and they show a
strong correlation with the levels of anti-DNA anti-
bodies. Thus, anti-DNA/NR2 antibodies in PSNP-
SLE are a dominant subset of anti-DNA antibodies.
Our findings suggest that anti-DNA/NR2 antibodies
may be a predictive factor not only in de novo
NPSLE but also in PSNP-SLE. The administration
of high doses of steroids in patients with SLE is
believed to trigger psychiatric symptoms.
7. Treatment of NPSLE
No clear evidence has yet been found regarding the
treatment of NPSLE. Various immunosuppressive

treatments have been introduced for a variety of NP
symptoms in patients with SLE (e.g. high-dose corti-
costeroids, methylprednisolone pulse therapy, intra-
venous immunoglobulins (IVIG), plasma exchange,
immunosuppressants, including cyclophosphamide,
azathioprine, mycophenolate mofetil (MMF) and
biologics represented by rituximab).
Cyclophosphamide is the only drug that has been
compared with steroid pulse therapy in a random-
ized controlled trial and has been found more useful
than steroid pulse therapy [48]. However, the evi-
dence from this study is considered insufficient due
to the characteristics of the patients. For instance,
most patients had epilepsy or peripheral neuropathy,
and some had optic neuritis. Azathioprine can be
used as a maintenance therapy or to reduce the ster-
oid dosage applied. Azathioprine used as a mainten-
ance therapy has been shown to suppress the
recurrence of NP manifestations in patients with
NPSLE [49]. MMF is widely used as the first-line
option for both the induction and maintenance
therapies for lupus nephritis. Several observational
studies have suggested the potential benefit of MMF
in the non-renal manifestations of SLE [50].
However, it is difficult to make any definite conclu-
sion. Rituximab is anti-CD20 IgG1 type 1 chimeric
monoclonal antibody that destroys B cells by specif-
ically targeting the CD20 molecules on their surfaces
[51]. The effectiveness of rituximab against refrac-
tory NPSLE has previously been reported by
Tokunaga et al. [52]. In a systematic review, clinical
response to rituximab has been detected in 85% of
patients with NPSLE [53]. However, two SLE
patients under rituximab treatment have died due to
progressive leukoencephalopathy, and thus the clin-
ical trial has been aborted. The evidence on the effi-
cacy of IVIG is limited. Case reports and
retrospective studies indicate that IVIG successfully
treats SLE patients with a broad spectrum of NP
symptoms [54]. Hydroxychloroquine is used as a
first-line drug in SLE patients who do not display
major organ disorders. This drug was finally
approved in Japan in 2015 and can now be adminis-
tered to patients with cutaneous SLE or those show-
ing rash, arthritis, myalgia, malaise or fever. It has
also been proposed for the primary prevention of
NPSLE, especially for cerebrovascular disorders
[3,55] and epileptic seizures [56].
8. Conclusion
NPSLE is one of the severe manifestations in SLE.
Because of the small patient number and severity of
the disease, it is hard to conduct RCTs for patients
with NPSLE. However, NPSLE was defined by the
ACR in 1999, and the guidelines for the
IMMUNOLOGICAL MEDICINE 139
management and treatment of NPSLE were pro-
vided by EULAR in 2010. The clinical framework of
NPSLE has gradually been established. In addition,
promising research efforts for novel targeted thera-
pies and improved diagnostic tools are in progress.
We believe there will be a better way to treat
patients for enhanced prognosis and quality of life.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
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