Neuropsychiatric systemic lupus erythematosus.

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the least understood, yet perhaps the most prevalent manifestation of lupus. The pathogenesis of NPSLE is multifactorial and involves various inflammatory cytokines, autoantibodies, and immune complexes resulting in vasculopathic, cytotoxic and autoantibody-mediated neuronal injury. The management of NPSLE is multimodal and has not been subjected to rigorous study. Different treatment regimens include nonsteroidal anti-inflammatory drugs, anticoagulation, and immunosuppressives such as cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate. For refractory NPSLE, intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab have been used. Adjunctive symptomatic treatment complements these therapies by targeting mood disorders, psychosis, cognitive impairment, seizures or headaches. Several new biological agents are being tested including Belimumab, a human monoclonal antibody that targets B lymphocyte stimulator. This review focuses on the pathophysiology, treatment, and new potential therapies for neuropsychiatric manifestations of systemic lupus erythematosus.

Full text

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Current Neuropharmacology, 2011, 9, 449-457 449
1570-159X/11 $58.00+.00 ©2011 Bentham Science Publishers
Neuropsychiatric Systemic Lupus Erythematosus
Alexandra Popescu1,* and Amy H. Kao2
1Department of Neurology, Epilepsy Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;
2Lupus Center of Excellence, Department of Medicine, Allegheny Singer Research Institute, West Penn Allegheny Health
System, Pittsburgh, PA, USA
Abstract: Neuropsychiatric systemic lupus erythematosus (NPSLE) is the least understood, yet perhaps the most preva-
lent manifestation of lupus. The pathogenesis of NPSLE is multifactorial and involves various inflammatory cytokines,
autoantibodies, and immune complexes resulting in vasculopathic, cytotoxic and autoantibody-mediated neuronal injury.
The management of NPSLE is multimodal and has not been subjected to rigorous study. Different treatment regimens
include nonsteroidal anti-inflammatory drugs, anticoagulation, and immunosuppressives such as cyclophosphamide,
azathioprine, mycophenolate mofetil, and methotrexate. For refractory NPSLE, intravenous immunoglobulin (IVIG),
plasmapheresis, and rituximab have been used. Adjunctive symptomatic treatment complements these therapies by target-
ing mood disorders, psychosis, cognitive impairment, seizures or headaches. Several new biological agents are being
tested including Belimumab, a human monoclonal antibody that targets B lymphocyte stimulator. This review focuses
on the pathophysiology, treatment, and new potential therapies for neuropsychiatric manifestations of systemic lupus
erythematosus.
Keywords: SLE, neuropsychiatric lupus, immunosuppression, autoimmunity, autoantibody.
I. INTRODUCTION

rected immune system reacts against host antigens. The dys-
regulation of the immune system may precipitate dysfunction
and damage of various organ systems, including the central
and peripheral nervous systems. We are reviewing patho-
physiology of neuropsychiatric involvement in systemic
lupus erythematosus (SLE) and its therapy. Most of the clinical
manifestations of disease are nonspecific complicating the
diagnosis, clinical assessment and treatment planning.
An autoimmune disease is a disorder in which the misdi-
II. CLINICAL FEATURES AND EPIDEMIOLOGY

women of child-bearing age. In the United States, SLE is
more prevalent among African Americans, Hispanics, and
Asians compared to non-Hispanic Caucasians [1]. This het-
erogeneous autoimmune disease is characterized by the loss
of tolerance to autoantigens and the development of immune
complexes that deposit in tissues and cause systemic in-
flammation. SLE also involves a number of cytokine path-
ways, including B lymphocyte stimulator (BLys), which
promotes B-cell survival and autoantibody production, type I
interferon (IFN), which acts as immune adjuvant, and tumor
necrosis factor, which contributes to organ inflammation.
Type I IFNs are normally produced by plasmacytoid den-
dritic cells in response to viral infection. However, patients
with SLE have an increased expression of type I IFN regu-
lated genes due to the continuous production of IFN-?. Their
dendritic cells activated by immune complexes containing
endogenous nucleic acids are also induced to synthesize IFN

SLE is an autoimmune disease that predominantly affects
*Address correspondence to this author at the 3471 Fifth Ave #811, Pittsburgh,
PA 15213, USA; Tel: 412-692-4920; Fax: 412-692-4636;
E-mail: popescua@upmc.edu
that contributes to loss of tolerance and activation of autore-
active T and B cells with production of autoantibodies [2-4].
SLE patients have elevated serum levels of IFN-?, which
correlate with both disease activity and severity [5, 6]. Based
on this knowledge, many clinical trials targeting cytokines as
potential therapies for SLE are underway.

yet perhaps the most prevalent manifestations of lupus. It
affects 14% to over 80% in adults [7-12] and 22% to 95% in
children [11, 13-16] and can occur independently of active
systemic disease and without serologic activity [17]. NSPLE
is associated with increased morbidity and mortality [7-9, 18,
19]. In 1999, the American College of Rheumatology (ACR)
established case definitions for 19 specific neuropsychiatric
syndromes, dividing them into two broad categories: central
and peripheral as shown in Table 1 [20]. In NPSLE, cogni-
tive impairment is one of the most common manifestations,
with a varying prevalence of 15% to 66% due to the differ-
ences in definition in the studies of mainly adult lupus pa-
tients [21-25]. Seizure and psychosis, however, are the only
two NPSLE manifestations that comprise the neurologic
component of the ACR classification criteria for SLE [26,
27]. It is estimated that 28% to 40% of adult NPSLE mani-
festations develop before or around the time of the diagnosis
of SLE and 63% occur within the first year after diagnosis
[9, 19, 28].
Neuropsychiatric lupus (NPSLE) is the least understood
III. PATHOPHYSIOLOGY AND PATHOGENESIS OF
NEUROPSYCHIATRIC LUPUS

involve various inflammatory cytokines, autoantibodies, and
immune complexes resulting in vasculopathic, cytotoxic and
autoantibody-mediated neuronal injury. The most common
microscopic brain finding in SLE seems to be microvasculo-
The pathogenesis of NPSLE is multifactorial and can

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450 Current Neuropharmacology, 2011, Vol. 9, No. 3 Popescu and Kao
pathy although not specific, which may due to complement
activation and antiphospholipid antibodies [29]. Post mortem
histopathologic studies in people with SLE have demon-
strated an array of pathologies including multifocal microin-
farcts, gross infarcts, hemorrhage, cortical atrophy, ischemic
demyelination, and patchy multiple sclerosis–like demyeli-
nation [30].
Table 1. Neuropsychiatric Syndromes of Systemic Lupus
Erythematosus [11]
Central Nervous System
Aseptic meningitis
Cerebrovascular disease
Cognitive dysfunction
Headache
Movement disorder (Chorea)
Seizures
Acute confusional state
Anxiety disorder
Mood disorder
Psychosis
Demyelinating syndrome
Myelopathy (transverse myelitis)
Peripheral Nervous System
Autonomic disorder
Mononeuropathy
Cranial neuropathy
Plexopathy
Polyneuropathy
Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-
Barré syndrome)
Myasthenia gravis


neuropathology of SLE [31]. Endothelial cells responsible
for maintenance of the blood-brain barrier may have altered
function in the presence of elevated levels of ICAM-1, with
subsequent normalization of function corresponding to both
lower levels of ICAM-1 and disease remission [32]. Addi-
tionally, damage to the blood-brain barrier may be impli-
cated in corticosteroid-induced psychiatric disorders [33].
Diamond and colleagues have generated abundant evidence
from murine models, supporting the role of circulating anti-
DNA autoantibodies mediating NPSLE via cross-reactivity
with NR2 subunits of the anti-N-methyl-D-aspartate recep-
tors during a breach of blood-brain barrier from inflamma-
tion or stress [34-37]. This cross-reactive excitatory neuronal
death in the hippocampus was non-inflammatory by histopa-
Disruption of the blood-brain barrier is integral to the
thologic examination and could be prevented by the admini-
stration of memantine, a NR2 glutamate receptor antagonist
[36]. Similarly, epinephrine, a catecholamine, also breached
the blood-brain barrier and caused selective neuronal loss in
the lateral amygdala, leading to emotional disorder in the
murine model [35]. These studies suggest that agents such as
epinephrine can determine the region of brain that is made
vulnerable to neurotoxic autoantibodies.

rier seems to play a role in the pathophysiology of NPSLE,
there are several types of autoantibodies which are also asso-
ciated with NPSLE. In addition to the aforementioned anti-
NR2A glutamate receptor antibodies, intrathecal IgG produc-
tion is often elevated during a central nervous system flare,
and then normalizes with the resolution of the flare [38, 39].
This fluctuation in IgG levels is in contrast to the persistent
abnormal immunologic indices seen during a remission of
multiple sclerosis [40]. Moreover, approximately 25% to
40% of lupus patients have secondary antiphospholipid syn-
drome with clinical features of repeated episodes of arterial
or venous thrombosis, recurrent spontaneous abortions, or
thrombocytopenia in patients with antiphospholipid (aPL)
antibodies [41-45]. Of note, patients with primary aPL syn-
drome do not fulfill the criteria for SLE, or other autoim-
mune disorders. APL antibodies target anionic phospholipids
and protein-phospholipid complexes. Specifically, they can
target negatively charged phosphatidyl glycerol, phosphati-
dyl serine, phosphatidyl acid, phosphatidyl inositol, and car-
diolipin, in addition to the neutrally charged phosphatidyl
ethanolamine, phosphatidyl choline, platelet activating
factor, and sphingomyelin [46]. Using ELISA and lupus
anticoagulant tests, antibodies binding cardiolipin in the
presence of ?2-glycoprotein-1 and antibodies binding ?2-
glycoprotein-1 and prothrombin can be detected. Studies
have demonstrated aPL-mediated direct neuronal injury in
the absence of ischemia [47-50]. Persistently elevated anti-
cardiolipin antibodies are associated with greater cognitive
impairment [23, 24]. In a cohort of 1000 patients followed
over 10 years, Cervera and colleagues demonstrated an in-
creased risk of thrombotic events, the most common being
stroke which was observed in 11.8% of the cohort [51].
Among SLE patients with and without active disease both
thrombotic events and cognitive impairment have been con-
sistently linked to the presence of aPL, such as lupus antico-
agulant and anticardiolipin antibodies [21, 52-54]. Addition-
ally, transverse myelitis is highly associated with the pres-
ence of aPL [55]. Significant correlations between anticardi-
olipin IgG antibodies and a reduction in psychomotor speed,
and between anticardiolipin IgA antibodies and a reduction
in conceptual reasoning and executive ability have been
found [21]. While the role of these autoantibodies awaits
elucidation, they certainly can act as proxies for disease
markers which may aid in the diagnosis of NPSLE.
While interruption of the function of the blood-brain bar-

under ongoing investigation. In particular, the previously
mentioned anti-NR2 glutamate receptor antibodies are seen
in 25% to 30% of patients with SLE and may also play a role
in cognitive dysfunction and psychiatric disease [56, 57].
These antibodies are anti-DNA antibodies that cross-react
with the NR2 glutamate receptor and mediate excitatory
The pathophysiologic role of autoantibodies in NPSLE is

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Neuropsychiatric Systemic Lupus Erythematosus Current Neuropharmacology, 2011, Vol. 9, No. 3 451
apoptotic cell death of neurons in vitro and in vivo [37]. The
anti-ribosomal P antibodies, another potential contributors to
the pathogenesis of NPSLE, have not been implicated in
coexisting cognitive impairment [58, 59]. Some studies sug-
gested an association between serum anti-ribosomal P anti-
bodies and NPSLE syndromes of psychosis and depression
[59-63]. An international meta-analysis of 1,537 patients
with SLE found the negligible value of anti-ribosomal P an-
tibodies for the diagnosis of NPSLE or for specific NPSLE
manifestations [64]. The potential role of anti-ribosomal P
antibodies in the pathogenesis of NPSLE remains controver-
sial. A cellular protein found strictly in neurons and essential
to the cytoskeletal integrity is MAP-2. In a study of 100
patients with SLE and 74 patients with various neurologic
disorders, more SLE patients comparing to neurologic in-
jury/disease control patients have presence of anti-MAP-2
antibodies (17% vs. 4%, p=0.028 ) [65]. More specifically,
76.5% of NPSLE had presence of serum anti-MAP-2 anti-
bodies. Using immunoproteomics, MAP-2B proteins were
found to be preferentially recognized by sera from NPSLE
patients, which further supports this association between the
anti-MAP-2 antibodies and NPSLE [66]. The importance of
autoantibodies is still under active investigation and many of
the observations are based only on association.

matrix metalloproteinase-9 (MMP-9) and plasminogen acti-
vator inhibitor 1 (PAI-1). MMP-9 is secreted by cells found
in the walls of the vasculature, including macrophages, T
lymphocytes, endothelial cells, and smooth muscle [67]. Its
primary function is to enhance T cell migration through con-
nective tissue. Significantly elevated intrathecal levels of
MMP-9 are found in all patients with SLE comparing to non-
SLE patients and specifically, with more elevation in NPSLE
patients when compared with SLE patients without NPSLE
[68]. Furthermore, CSF levels of IL-6 and IL-8, which are
found to be elevated in NPSLE, are both significantly corre-
lated with MMP-9 levels. Similarly, intrathecal levels of
PAI-1 have been found to be significantly elevated in pa-
tients with NPSLE comparing to those without NPSLE and
healthy controls [69]. The intrathecal levels of PAI-1 also
correlated with CSF levels of proinflammatory cytokines,
IL-6 and IL-8, in addition to association with neuronal dam-
age markers, glial fibrillary acidic protein and neurofilament
triplet protein. The association between neuronal injury and
intrathecal homeostasis imbalance contributed by the release
of PAI-1 suggests a potential therapeutic role of anticoagula-
tion in patients with NPSLE even in the absence of the
antiphospholipid syndrome.
Other possible intrathecal markers for NPSLE include
IV. NEUROIMAGING MODALITIES

psychiatric symptoms in SLE continues to be elucidated with
brain imaging studies, though these modalities are not with-
out limitations. While focal neurologic symptoms of NPSLE
correlate with conventional structural magnetic resonance
imaging (MRI) abnormalities, abnormalities reflecting al-
tered perfusion or neurometabolite changes in NPSLE can be
demonstrated by functional imaging techniques even in the
absence of morphological lesions detectable by conventional
MRI. Cortical atrophy, ventricular dilation, diffuse white
matter, and gross infarctions are common [70-74]. Using
Localizing the areas of the CNS associated with neuro-
structural MRI, 40%–80% of abnormalities in NPSLE are
multiple discrete lesions concentrated in periventricular and
subcortical white matter [75]. These can also be seen in SLE
patients without past or active neuropsychiatric lupus [76].
Hippocampal atrophy correlates with disease duration, total
corticosteroid dose, and repeat CNS events in patients with
SLE [77]. The presence of hyperintense white matter lesions
in SLE is associated with age, total corticosteroid dose re-
ceived and Systemic Lupus International Collaborating Clin-
ics (SLICC) Damage Index scores [78]. Furthermore, predic-
tors for development of new or worsening of existing white
matter lesions include past CNS involvement, elevated titers
of aPL antibodies, SLICC Damage Index scores and higher
dose of total corticosteroid dose [78].

phy/PET, MR spectroscopy) and perfusion imaging (single
photon emission computer tomography/SPECT) can detect
abnormalities in patients who present exclusively with psy-
chiatric manifestations, but otherwise have normal MRI
studies. In fact, normal structural MRI studies do not exclude
active NPSLE as fluorodeoxyglucose-PET (FDG-PET) im-
aging can demonstrate parieto-occipital white matter hy-
pometabolism in 60% to 80% of patients [11, 79-81]. During
acute NPSLE, FDG-PET reveals white matter abnormalities
in the prefrontal, anterior cingulate, and inferior parietal re-
gions [11, 82, 83]. Such abnormalities rarely include tempo-
ral regions [79]. Consistent with the vasculopathic nature of
NPSLE, SPECT and proton MR spectroscopy (1H-MRS)
studies suggest that cerebral atrophy and cognitive impair-
ment in SLE patients may be related to chronic diffuse cere-
bral ischemia [17, 76, 84]. MRS is an MR technique that
determines the biochemical composition or neurometabolites
of brain tissues noninvasively. Reduced N-acetylaspartate
(NAA) levels may indicate neuronal injury or death whereas
increased choline (Cho) levels have been associated with
gliosis and membrane breakdown. 1H-MRS shows neurome-
tabolic abnormalities during both active and quiescent peri-
ods of NPSLE, most probably related to neuronal injury or
loss and demyelination [85, 86] More specifically, SLE pa-
tients with moderate or severe cognitive dysfunction had
significantly higher Cho/creatine (cr) as determined by 1H-
MRS compared to those with mild or no cognitive dysfunc-
tion, and SLE patients with active disease had low NAA/cr
that returned to normal range after disease remission. Con-
versely, patients with active SLE during follow-up devel-
oped significant reduction in NAA/cr [86]. Furthermore, in a
small study with follow-up after 4-6 years from baseline
evaluation, all new structural MRI lesions were anatomically
associated with the previously detected abnormal areas iden-
tified by SPECT and 1H-MRS [87]. This study is confirmed
by another group which also found neurometabolic changes,
specifically increased Cho/cr ratio, in normal appearing
white matter may predict future appearance of hyperintense
white matter lesions in SLE [88]. Lesions detected by MRI
have been shown to correlate with cognitive impairment
measured by neuropsychological testing in 72% of SLE pa-
tients (Kappa statistics for agreement=0.42, p=0.005) [89].
Finally, a recent study demonstrated the close postmortem
histopathologic association of premortem neurometabolite
abnormalities in NPSLE [90]. This was a prospective cohort
study of 168 patients with SLE who had 1H-MRS at baseline,
Metabolic neuroimaging (positron emission tomogra-

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452 Current Neuropharmacology, 2011, Vol. 9, No. 3 Popescu and Kao
during lupus flare, and at 3 years after enrollment. Correla-
tion of histopathology and imaging showed that: 1) elevated
Cho levels are independently associated with gliosis, vascu-
lopathy and edema; 2) reduced NAA levels are associated
with reduced neuronal-axonal density; and 3) presence of
lactate correlates with necrosis, microhemorrhage, and
edema [90].

nique that has been used to assess for cognitive function in
SLE. Formal neuropsychological testing and fMRI using 3
paradigms (continuous performance task, N-back task and
verb generation) were assessed in a pilot study of 10 patients
with childhood-onset SLE [91]. Compared to the control
group, the SLE group demonstrated significantly increased
activation of brain areas involved in the 3 paradigms. More
importantly, in the absence of active stimuli, SLE patients
consistently undersuppressed activity in the expected brain
area. These findings support the notion that the imbalance
between active and inhibitory responses to stimuli in child-
hood-onset SLE may be associated with abnormalities in
white matter connectivity resulting in neuronal network dys-
function.
Functional MRI (fMRI) is another neuroimaging tech-

derstanding of NPSLE, which appears to be caused by acute
and chronic brain injury caused by SLE and are promising
approaches to elucidate the areas and mechanisms involved
in NPSLE and specific manifestation as in cognitive dys-
function.
Neuroimaging modalities have greatly advanced the un-
V. TREATMENT

and continues to be a major therapeutic challenge due to the
broad spectrum of the NPSLE manifestations and limitations
in diagnostic testing. Currently, only three medications are
FDA-approved for treatment of SLE in the United States:
glucocorticoids, aspirin, and hydroxychloroquine. Glucocor-
ticoids are one of the primary therapeutics in the manage-
ment of NPSLE. Treatment choices tend to vary and are tai-
lored to individual patient’s clinical presentation, disease
severity, and potential pathogenic mechanism. For example,
thrombosis with the presence of antiphospholipid antibodies
would indicate the need for anticoagulation. Medication use
can range from nonsteroidal anti-inflammatory drugs for
symptomatic relief, anticoagulation for thrombotic diseases,
to the immunosuppressives for inflammation such as cyclo-
phosphamide, azathioprine, mycophenolate mofetil, and
methotrexate [92]. Evidence for the efficacy of these thera-
pies is limited to uncontrolled clinical trials and anecdotal
experience [93]. Adjunctive symptomatic treatment com-
plements these therapies by targeting mood disorders, psy-
chosis, cognitive impairment, seizures or headaches. Mild
NPSLE may only need symptomatic treatment. Treatment
strategies should include identification and treatment of any
secondary causes of CNS dysfunction such as infection, in-
creased intracranial pressure, medication side effects, or pri-
mary psychiatric disorders.
The management of patients with NPSLE is multimodal

are one of the three FDA-approved drugs for the treatment of
SLE; currently in the United States, as many as 90% of SLE
patients are treated with glucocorticoids [11]. The treatment
Glucocorticoids (e.g. prednisone, methylprednisolone)
with glucocorticoids is widely used in the management of
seizures, refractory headache, chorea, transverse myelitis and
other CNS manifestations of SLE. Glucocorticoids are used
in high doses orally (1-2 mg/kg by mouth daily), or intrave-
nously (usually 1 gram daily for 3 days, followed by daily
high-dose oral glucocorticoids) for acute and severe flares.
Many patients require chronic immunosuppressive therapy in
order to suppress SLE disease activity. Treatment with glu-
cocorticoids carries long-term morbidity and numerous well-
known side effects including dyslipidemia, diabetes, hyper-
tension, accelerated cardiovascular disease, and increased
susceptibility to infection and osteoporosis. In addition, these
drugs can induce adverse effects on cognitive functioning
and psychiatric symptoms [22, 94]. Therefore, in order to
avoid these potential side effects, patients are administered
the lowest possible dose of the glucocorticoids.

have suspected immunomodulatory properties that may also
provide lipid-lowering and antiplatelet effects, thus prevent-
ing thromboembolic events [95]. Hydroxychloroquine can be
used as maintenance therapy to prevent disease flare and
may also improve fatigue and possibly cognitive dysfunc-
tion. Hydroxychloroquine is considered the safest of the an-
timalarials and can be continued during pregnancy. The ini-
tial dose is 200 mg daily with a maintenance dosage of 200
to 400mg daily but less than 6.5 mg/kg ideal body weight.
The main side effects include irreversible retinopathy and
glucose-6-phosphate dehydrogenase-induced
Toxic myopathy can be seen in antimalarial use with the
presence of curvilinear bodies by electron microscopy in
muscle biopsy specimens [96].
Antimalarial drugs, specifically hydroxychloroquine,
hemolysis.

out immunosuppressives in NPSLE related to thrombosis
and the presence of aPL antibodies. Furthermore, anticoagu-
lation may also be used to treat refractory headache in pa-
tients with aPL antibodies. Antiplatelet agents, especially
aspirin, have also been prescribed in patients with aPL anti-
bodies but without a history of thrombosis. Stratification of
the risks of thrombosis, smoking cessation and the use of
protective medications such as aspirin and antimalarials are
important elements of thrombosis prevention in SLE.
Anticoagulation is the mainstay of therapy with or with-

toxic alkylating agent used in organ-threatening disease in
SLE and other autoimmune disorders. Severe NPSLE mani-
festations, mainly CNS involvement like cerebrovascular
disease due to inflammation and transverse myelitis, has
been treated with cyclophosphamide. There are different
regimens of cyclophosphamide, which are mainly studied for
treatment of lupus nephritis [97]. Cyclophosphamide can be
given as monthly intravenous (500–1000 mg/m2) doses for a
6-month induction period followed by quarterly maintenance
doses for a period of 2 years [55, 98]; however, studies have
shown that immunosuppressives with less toxicity can be
used for maintenance. Monthly intravenous cyclophos-
phamide was found to be superior to methylprednisolone in a
small, randomized, clinical trial in controlling refractory
seizures, peripheral and cranial neuropathy, and optic neuri-
tis with a similar incidence of new infections [99]. In the
Euro-Lupus Nephritis trial, lower dosage of intravenous
cyclophosphamide at 500 mg has been given biweekly for 3
Cyclophosphamide is an immunosuppressive and cyto-

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Neuropsychiatric Systemic Lupus Erythematosus Current Neuropharmacology, 2011, Vol. 9, No. 3 453
months for treatment of proliferative lupus nephritis.
This study found comparable clinical results of this low-dose
intravenous cyclophosphamide (cumulative dose of 3 gram)
followed by azathioprine and the high-dose group
(6 monthly pulse cyclophosphamide followed by 2 quarterly
pulses) [100]. The most important side effects of cyclophos-
phamide include susceptibility to a variety of opportunistic
infections, hemorrhagic cystitis from acrolein (toxic metabo-
lite), increased risk of malignancy (non-Hodgkin lymphoma,
leukemia, and transitional cell carcinoma of the bladder), and
potential ovarian or testicular failure [101]. Due to the toxic-
ity of cyclophosphamide, the current view is that cyclophos-
phamide should be used for shorter duration with a lower
dose if possible and not be continued for maintenance ther-
apy. Immunosuppressives with better side effect profile, such
as mycophenolate mofetil (MMF), have been used frequently
for maintenance and even initial treatment of NPSLE mani-
festations.

been used in systemic lupus erythematosus to treat a variety
of manifestations or have been used as glucocorticoid-
sparing agents, but controlled trials are lacking [102].
Azathioprine, methotrexate, and MMF are antimetabolites,
which inhibit de novo synthesis of purine and/or pyrimidine
[103]. Azathioprine is a prodrug that is rapidly and almost
completely converted to 6-mercaptopurine (6-MP) and
methylnitroimidazole. Further metabolism of 6-MP inhibits
several enzymes of purine synthesis. Methotrexate and its
polyglutamate derivatives suppress inflammatory response
through release of adenosine, suppress immune response by
inducing the apoptosis of activated T lymphocytes and inhib-
iting the synthesis of both purines and pyrimidines. MMF is
a prodrug of mycophenolic acid (MPA) and an inhibitor of
inosine-5’-monophosphate dehydrogenase. MPA depletes
guanosine nucleotides preferentially in T and B lymphocytes
and inhibits their proliferation, thereby suppressing cell-
mediated immune response and antibody formation. MPA
also inhibits the expression of adhesion molecules and the
recruitment of immune cells (lymphocytes and monocytes)
into sites of inflammation. MMF has been used to reduce
acute and chronic rejection in allograft recipients. MMF
showed a significantly higher remission rate than intravenous
cyclophosphamide in renal lupus [104]. However, in a large
international randomized controlled trial, MMF (target dos-
age 3 grams/day orally) and intravenous cyclophosphamide
(0.5 to 1 gram/meter2 in monthly pulses) have similar effi-
cacy to short-term induction therapy (24 weeks) for active
lupus nephritis [105]. Of note, more Black and Hispanic pa-
tients responded to MMF than intravenous cyclophos-
phamide [106]. MMF has also shown to be efficacious in
non-SLE patients with multiple sclerosis and optic neuritis
by reducing the relapse rate [107, 108]. These noncytotoxic
immunosuppressives are more commonly used in NPSLE
patients with peripheral nervous system involvement such as
peripheral and cranial neuropathy. Furthermore, MMF may
be used as maintenance therapy after initial treatment with
cyclophosphamide in patients with severe NPSLE.
Other agents such as azathioprine and methotrexate have

and rituximab have been used in central nervous system
manifestations unresponsive to glucocorticoid therapy and/or
cytotoxic therapy. IVIG has immunomodulatory effects by
Intravenous immunoglobulin (IVIG), plasmapheresis,
interaction with the anti-idiotypic network, interference with
the complement and cytokines’ network, cytolysis of target
cells through complement or antibody-dependent cell-
mediated cytotoxicity and induction of apoptosis of target
cells through Fc receptors, neutralization of pathogenic anti-
bodies and modulation of the activation and co-stimulatory
molecules affecting differentiation of T cells, B cells, and
dendritic cells [109]. IVIG also suppresses the expansion of
auto-reactive B lymphocytes through signaling of the
FcgRIIB, idiotype-mediated inhibition of B cell receptors
and neutralization of cytokines such as the B cell survival
factors. IVIG has been given as 2 gm/kg with divided doses
over two to five days to treat thrombocytopenia, renal dis-
ease, central nervous system manifestations, and pregnancy
loss associated with the presence of antiphospholipid
antibodies [110]. Plasmapheresis, administered four to six
sessions over one to two weeks, may be another option for
the treatment of NPSLE manifestations [92]. The rationale of
plasma exchange is based on the rapid removal of circulating
pathogenic autoantibodies, immunoglobulins, immune com-
plexes, and toxins. One study showed a significant elevation
of peripheral CD4+ CD25 high FoxP3+ suppressor T cells in
SLE patients treated with repeated plasmapheresis resulting
in significant clinical improvements, thereby suggesting the
increase in regulatory T cells may be one of the reasons of
the beneficial effects of plasmapheresis in SLE patients
[111]. Rituximab, chimeric anti-CD20 monoclonal antibod-
ies that deplete CD20+ B cell, has shown to be efficacious in
treatment of refractory SLE in case reports including those
with transverse myelitis and CNS vasculitis [112, 113].
Adjunctive Medications Commonly Used for Sympto-
matic Treatment

should also be treated with a combination of symptomatic
and immune-modulating therapy. Seizures are managed with
standard anticonvulsants. Although these medications have
been implicated in drug-induced lupus, they do not appear to
alter idiopathic disease. The nonsteroidal anti-inflammatory
drugs (NSAIDs) suppress mild acute inflammation alleviat-
ing musculoskeletal manifestations, fatigue and fever.
NSAIDs can alleviate migraine headache frequently seen in
patients with SLE. However, chronic NSAIDs use can also
aggravate headache. They may be administered alone or
given in combination with glucocorticoids, allowing a de-
crease in glucocorticoid dosage. There are numerous options
when choosing NSAIDs and effectiveness varies widely,
therefore doses should be individualized. The adverse effects
of NSAIDs include nonsteroidal-induced nephropathy, gas-
trointestinal bleeding, and ibuprofen-induced aseptic menin-
gitis [92]. Psychotropic medications (antidepressants, anx-
iolytics, and atypical antipsychotics) may have an important
adjunctive role in SLE patients with affective disorder or
psychosis. There is no standardized treatment in lupus psy-
chosis. The treatment for acute psychosis includes a combi-
nation of antipsychotic medications as symptomatic treat-
ment and glucocorticoids to control underlying disease activ-
ity [114, 115]. Steroid-induced psychosis can be seen in pa-
tients already on this medication. A temporal relationship
between the initiation of glucorticoids and psychiatric
events, and the resolution of psychiatric symptoms after re-
duction of glucorticoids is the main clinical feature in diag-
NPSLE manifestations, such as seizures and headaches,