Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Pharmacologic management of neuropsychiatric

lupus

Shaye Kivity, Britain Baker, Maria-Teresa Arango, Joab Chapman & Yehuda
Shoenfeld

To cite this article: Shaye Kivity, Britain Baker, Maria-Teresa Arango, Joab Chapman & Yehuda
Shoenfeld (2015): Pharmacologic management of neuropsychiatric lupus, Expert Review of
Clinical Pharmacology, DOI: 10.1586/17512433.2016.1111137

To link to this article: http://dx.doi.org/10.1586/17512433.2016.1111137

Published online: 11 Nov 2015.

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 Review

Pharmacologic management
of neuropsychiatric lupus
Expert Rev. Clin. Pharmacol. Early online, 1-6 (2015)

Shaye Kivity1,2,3,4, Neuropsychiatric lupus affects above 50% of patients with systemic lupus erythematosus and
Britain Baker1,5, may span from mild symptoms to acute devastating life-threatening ones. Owing to the
Maria-Teresa Arango1,6, clinical variability, most pharmacological data rely on small, uncontrolled trials and case
Downloaded by [Chinese University of Hong Kong] at 19:37 19 November 2015

reports. The mainstay of therapy relies on immune-suppression by glucocorticoids, in adjunc-

Joab Chapman7,8 and
tion with cyclophosphamide or anti-B-cell therapy, in moderate to severe cases. In selected
Yehuda Shoenfeld*1,8,9 scenarios (e.g., chorea) intravenous immunoglobulin or plasmapheresis may be effective.
1
The Zabludowicz Center for Anticoagulation is warranted if anti-phospholipid antibodies are present. In parallel there
Autoimmune Diseases, The Chaim
Sheba Medical Center, Tel-
may be a need for symptomatic treatment such as anti-epileptic or anti-depressive treatments,
Hashomer, Ramat-Gan, Israel etc. In the future, more studies addressed to assess pathogenesis and preferred treatments of
2
Rheumatology Unit, The Chaim specific manifestations are needed in order to personalize treatments.
Sheba Medical Center, Tel
Hashomer, Ramat-Gan, Israel KEYWORDS: Anti-ribosomal P antibodies ● cyclophosphamide ● depression ● neuropsychiatric lupus ● systemic lupus
3
Department of Medicine ‘A’, The erythematosus
Chaim Sheba Medical Center, Tel
Hashomer, Ramat-Gan, Israel
4
The Dr. Pinchas Borenstein Talpiot
Medical Leadership Program 2013,
The Chaim Sheba Medical Center, Tel Systemic lupus erythematosus (SLE) is a com- while much less demonstrate a small vessel
Hashomer, Ramat-Gan, Israel
5
St Georges University of London/
plicated autoimmune disease affecting women thrombotic vasculopathy on postmortem stu-
Nicosia Medical School, University of of childbearing age. The systemic inflammation dies.[4] Other evidence suggests the involve-
Nicosia, Egkomi, Cyprus associated with SLE is characterized by ment of autoantibodies and immune
6
Doctorate Program of Universidad
del Rosario, Bogotá, Colombia
immune complex deposition in tissues and complexes that mediate neuronal injury,[2,7]
7
Department of Neurology, Sagol loss of tolerance to autoantigens. It is estimated following the disruption of the blood–brain
Neuroscience Center, Sheba Medical that SLE affects roughly 50 per 100,000 people barrier (BBB).[8] In addition cytokines and
Center, Tel-Hashomer, Ramat Gan,
Israel
depending on the population.[1] chemokines, such as IL-8, CCL5, MCP-1,
8
Sackler Faculty of Medicine, Tel-Aviv Neuropsychiatric systemic lupus erythematosus CXCR4/CXCL12 and CXCL10, are increased
University, Tel-Aviv, Israel (NPSLE) is an umbrella term used to describe in cerebrospinal fluid of NPSLE patients.[9–
9
Incumbent of the Laura Schwarz-
Kipp Chair for Research of
the wide range of central and peripheral ner- 12] Moreover, anti-phospholipid antibodies
Autoimmune Diseases, Tel-Aviv vous system complications of SLE. NPSLE is (aPLs) have a significant role in NPSLE, espe-
University, Tel-Aviv, Israel associated with both increased morbidity and cially in patients with thrombotic
*Author for correspondence:
Tel.: 972-3-5308070
mortality.[2] A study of 2049 SLE patients manifestations.
Fax: 972-3-5352855 found that as many as 56% of them had symp-
shoenfel@post.tau.ac.il toms of NPSLE. The disease is different from Diagnosis
other aspects of SLE in that it can occur inde- When a patient with an established diagnosis of
pendently of disease activity and without any SLE begins to suffer from neuropsychiatric ill-
serological changes.[3] In 1999 a task force of nesses, other causes must be first ruled out
the American College of Rheumatology before NPSLE can be ruled in. These causes
defined 19 case definitions for NPSLE, include non-SLE intercurrent infectious illness,
Table 1.[4,5] medication side effects (especially steroids) and
psychosocial- or functional-related conditions.
Pathophysiology [4] Once NPSLE is suspected, certain antibo-
The complex pathophysiology of NPSLE is dies may help with diagnosis, including anti-
mainly unknown, and varies from case to phospholipid, anti-ribosomal-P, anti-neuronal
case. Approximately 50% of the patients have and anti-ganglioside antibodies.[4,13] Other
evidence of brain white or gray matter lesions methods of diagnosis include psychological
via magnetic resonance imaging (MRI),[6] testing [14] and specific brain imaging mainly

www.tandfonline.com 10.1586/17512433.2016.1111137 © 2015 Taylor & Francis ISSN 1751-2433 1

 Review Kivity et al.

Table 1. 1999 ACR case definitions in NPSLE. commonly represent an active inflammatory process, but rather
associated conditions or sequel of previous events. In these cases,
Box 1 Nineteen case definitions for neuropsychiatric lupus
neuropsychiatric symptoms are treated with anti-epileptic, anti-
syndrome
depressive, anti-anxiolytic, anti-neuropathic, and other medica-
Central nervous Peripheral nervous system tions.[4] There are no preferred medications in these patients,
system
and they should be treated as any other neuropsychiatric
1. Headache 1. Mononeuropathy patient.
2. Seizure disorders 2. Polyneuropathy
3. Cerebrovascular 3. Cranial neuropathy Glucocorticoids
disease Glucocorticoids (GCs) are the mainstay of immunosuppressive
4. Demyelinating 4. Acute inflammatory demyelinating therapy lupus. It is estimated that as many as 90% of SLE
syndrome polyradiculopathy (Guillain–Barré patients are treated with GCs within the US. They are also
syndrome) the most effective primary treatment option to date with as
5. Myelopathy
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many as 60–70% of SLE patients responding to GCs.[4] In

6. Movement disorder 5. Plexopathy
7. Aseptic meningitis 6. Autonomic disorder
8. Cognitive dysfunction 7. Myasthenia gravis
9. Mood disorder
10. Anxiety disorder
11. Psychosis
12.Acute confusional
state
Note: Case definitions are based on the 1999 American College of Rheumatology
recommendations in neuropsychiatric lupus syndrome.
via computerized tomography (CT) and MRI.[4,15,16] Newer
imaging modalities such as single photon emission computed
tomography (SPECT) and positron emission tomography–CT
and magnetic resonance spectroscopy (MRS) are still being
studied and validated.[3]
Treatment
The treatment of NPSLE presents several obstacles to the clin-
ician. First, the difficulty to differentiate psychiatric symptoms
unrelated to SLE itself, from true immune-mediated NPSLE
symptoms. Second, the manifestations of NPSLE may vary
considerably, spanning from mild symptom such as headache
to life-threatening symptoms such as stroke or delirium. Each
manifestation may represent a different underlying pathogenic
mechanism, and therefore may require a different treatment.
Currently randomized control trials (RCTs) aimed at evaluating
specific treatments for each NPSLE manifestation are limited,
and treatment strategies in the majority of cases are based on
expert recommendations, case studies and small control trials.
Third, patients with SLE may have an overlap with another
autoimmune disease such as Sjogren’s syndrome, multiple
sclerosis, Devic syndrome, and others, which mask symptoms
and confuse clinicians.[4]
Nonimmune treatments
In parallel to immune-suppressive treatments (see below), in
some NPSLE patients there may be a need to control symptoms
such as depression, headaches or recurrent seizures which do not
NPSLE, GCs are considered the most effective immediate ther-
apy available and used to treat seizures, refractory headache,
chorea, transverse myelitis, and other NPSLE manifestations.
[2] The treatment involves IV pulse therapy for severe symp-
toms (e.g., 1 g solu-medrol/day for 3–5 days) followed by oral
treatment (e.g., prednisone 1 mg/kg/day). Although in debate,
in selected cases, low dose GCs (e.g., 5–10 mg prednisone) may
help to control mild nonspecific symptoms such as weakness
and tiredness. Common side effects of GC use include avascular
osteonecrosis, osteoporotic fractures, diabetes mellitus or catar-
acts, while CNS side effects include decreased cognition, as well
as potential psychiatric symptoms.[17] Although the side effects
of prolonged GC use are quite severe, when used properly under
heavy supervision, the benefit outweighs the risks associated
with GCs, as multiple organs are protected through its use.[17]
Antimalarials
Antimalarial (AM) agents, specifically hydroxychloroquine, are
widely used in treatment of SLE.[18] Hydroxychloroquine is
the safest of all AMs, and is considered safe in pregnancy. Strong
evidence from the literature suggests that AMs can be used as
maintenance therapy to prevent disease flare and may also
improve fatigue, as well as increase long-term survival, irrever-
sible organ damage and thrombosis.[19] AMs are not considered
a treatment for NPSLE; however, epidemiological studies sug-
gest they may prevent CNS flares,[20] protect against worsening
of brain lesions via MRI,[21] protect from seizures,[22] but not
from headaches.[23] In addition, in the context of aPL anti-
bodies leading to cerebrovascular diseases, AMs diminish the
risk for thrombosis by reduction in red blood cell sludging,
blood viscosity and platelet aggregation.[20] It should be
noted that Chloroquine, an older AM which has been with-
drawn, can cause behavioral changes as well as psychosis.
Cyclophosphamide
Cyclophosphamide (CYC) is often used to treat moderate to
severe NPSLE, and enables GC tapering down. There have been
limited RCT studies evaluating the efficiency of CYC in
NPSLE: one controlled clinical trial found that the addition of
IV CYC to methylprednisolone in a cohort of 32 patients with
NPSLE was more effective at preventing refractory seizures,

2 Expert Rev. Clin. Pharmacol.

 Pharmacologic management of neuropsychiatric lupus
cranial or peripheral neuropathy, optic neuritis, transverse mye-
litis, brainstem disease and coma than treatment with methyl-
prednisolone treatment on its own.[24] An additional study of
37 NPSLE patients treated with low doses of IV CYC (200–
400 mg per month) demonstrated a significant symptomatic
improvement when compared with patients treated with pre-
dnisone and AMs.[25] CYC has a range of side effects including
myelosuppression, GI disturbance, hemorrhagic cystitis, hair
loss, ovarian fibrosis and testicular atrophy. These side effects,
coupled with the limited data on its effectiveness, should be
taken into consideration when choosing to treat patients
with CYC.
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Azathioprine
Azathioprine is a GC-sparing immunosuppressive drug which is
normally used in treatment of SLE. Azathioprine is converted to
6-mercaptopurine and methylnitroimidazole, leading to the
inhibition of several enzymes involved in purine synthesis.[2]
Azathioprine may be used in NPSLE as maintenance therapy
after induction with CYC and GCs; however, its efficacy and
safety have not been systematically evaluated.[26,27] Further
studies should be undertaken to verify the effectiveness of
azathioprine in maintenance therapy for patients with NPSLE.
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is a GC-sparing immunosup-
pressive drug that is often used in conjunction with corticoster-
oids in treatment of lupus. Traditionally MMF has been used as
an immunosuppressant for transplant recipients. However, clin-
icians are increasingly using MMF as a treatment for lupus,
mainly lupus nephritis.[28,29] Recently, several case reports
have shown MMF to improve extra-renal pathologies associated
with SLE, including some NPSLE manifestations.[30,31] The
role of MMF for patients with NPSLE should be further
studied.
Anti-B-cell therapy
B cells are strong mediators in the pathogenesis of lupus and
their modulation was suggested to play a role in managing
disease activity. Anti-B-cell drugs pose high expectations for
treating SLE, as well as NPSLE, especially the anti-CD20
drug rituximab.[32,33] According to a systematic review of
the literature from 2014, which included 1231 SLE patients,
rituximab is safe and effective in the treatment of nonrenal SLE.
However in this review, the evidence for patients with neurop-
sychiatric involvement was weak.[34] In contrast, a systematic
review of 35 separate well-documented case reports and non-
controlled trials of patients with severe refractory NPSLE who
were treated with rituximab found a complete or partial
response in 85% of patients.[35] The patients demonstrated
clinical and serological improvement in parallel to significant
reduction of corticosteroid doses. A 45% relapse was noted,
suggesting that repeated therapy with rituximab is warranted.
[35] Belimumab, a fully human monoclonal antibody directed
against B-cell activating factor, was approved by the US FDA
www.tandfonline.com
Review
for SLE in 2011. However the major belimumab studies
(BLISS-52 and BLISS-72) excluded patients with active
NPSLE.[34,36] A later post hoc analysis performed for both
trials demonstrated clinical improvements in organ systems
with a low prevalence, including the CNS.[37] There still
remains little evidence regarding the use of anti-B-cell therapies
in treatment of NPSLE.
Intravenous Immunoglobulin/plasmapheresis
Treatment aimed to reduce autoantibody levels, such as plas-
mapheresis, is used in selected cases of NPSLE in which high
autoantibody levels are thought to correlate with disease activity.
In one retrospective study, plasmapheresis, in addition to CYC
and GCs, led to a complete remission in 54% of 10 NPSLE
patients.[38] The advantage of intravenous immunoglobulin
(IVIg) is its ability to modulate the immune system without
suppressing it. The role of IVIg for NPSLE had been studied in
several noncontrolled studies. In one small study (n = 9), IVIg
was effective and safe for NPSLE patients with mood swings
and cognitive disorders.[39]
Anti-aggregation/anticoagulation
Thrombosis is a common culprit in the pathogenesis of NPSLE,
especially in patients who are aPL antibody positive.
Thrombosis can be prevented with the use of anticoagulation/
anti-aggregation therapy and is indicated when there is clinical
and radiographic evidence of a thrombotic or an ischemic event.
It is currently recommended to treat all SLE patients with aPL
antibodies with anti-aggregation therapy as a primary preventa-
tive measure. Anticoagulants, on the other hand, should be
reserved as a secondary preventative measure.[40,41]
Conclusions
Treating NPSLE is a complex task for a clinician which needs to
combine knowledge from several disciplines including rheuma-
tology immunology, internal medicine, psychiatry and pharma-
cology. Today the mainstay of treatment relies on GCs as well as
other cytotoxic therapies which are associated with substantial
side effects. Newer biological treatments aimed to target ele-
ments of the immune system of NPSLE patients may help to
focus treatment, and minimize side effects. The efficacy of
removing or neutralizing autoantibodies by IVIg or plasmapher-
esis should by studied. There is a need for defining pathogenic
pathways in NPSLE, and to further establish the role of new
and old therapies in this group of patients.
Expert commentary & five-year view
Neuropsychiatric lupus encompasses a spectrum of clinical man-
ifestations which most probably reflect a set of impaired
immune pathways. We currently lack sufficient understanding
of the mechanisms which are involved in NPSLE, or under-
standing of the specific mechanisms of each manifestation.
Current research focuses on defining which pathway is involved
in each manifestation. New therapies directed at these mediators
may be of value in NPSLE. For example, ribosomal-P is an
3
 Review Kivity et al.

autoantibody which is related to depression and psychosis in
NPSLE patients. It is speculated that anti-ribosomal-P enters
the brain following a breached BBB, thus mediating neuronal
injury. Therapies aimed to block or modulate brain-autoanti-
bodies such as anti-ribosomal-P may emerge in the future.
Moreover, several autoimmune conditions including NPSLE
are related to high levels of cytokines and chemokines, such as
interleukin-6.[10,42,43] Blocking agents of these elements may
help generate new drugs. Other agents may be aimed to dimin-
ish BBB disruption, such as blocking the TWEAK/Fn14 path-
way. Mouse models, especially MRL-lpr female mice, can be
used for studying the pathogenesis of NPSLE in an experimental
setting.[44] RCTs should be aimed to test available therapies
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and MRS are currently tested, and may be used to provide
clinicians with better tools to diagnose and monitor treatment.
New biomarkers (blood tests or bio-imaging) will help monitor
treatment efficacy and assist differentiation between ‘true’
NPSLE patients and SLE patients with psychological or medi-
cation-related neuropsychiatric side effects. In the next 5 years
combining basic research, with RCTs, and new technologies
may help to personalize treatments for an individual NPSLE
patient.
Financial & competing interests’ disclosure
The author has no relevant affiliations or financial involvement

(e.g., rituximab, belimumab) in accordance with specific
NPSLE manifestations. However, this is a very difficult task
due to the number of patients that may be needed for each trial,
and may require cooperation between centers from several
countries. New technologies and modalities such as SPECT
with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honor-
aria, stock ownership or options, expert testimony, grants or patents
received or pending, or royalties.

Key issues
1. First exclude non-systemic lupus erythematosus intercurrent infectious illness, medication side effects (especially steroids), and
psychosocial- or functional-related conditions.
2. In neuropsychiatric systemic lupus erythematosus (NPSLE), glucocorticoids are the main treatment, sparing agents are often
used (e.g. azathioprine).
3. In the moderate to severe cases, cyclophosphamide or B-cell depletion is needed in adjunct to glucocorticoids.
4. In selected cases adding anticoagulants (when anti-phospholipid antibodies are present), plasmapheresis, or intravenous
immunoglobulin is effective.
5. There may be a need for symptomatic treatments in parallel to immunosuppressive ones (anti-depressive, anti-anxiolytic, ant-
epileptic, etc.)
6. Current treatments are based on sparse evidence; further randomized controlled trials must be done in order to gain a better
understanding of available treatment options.
7. The mechanisms behind the 19 different manifestations of NPSLE must be better understood in order to have more focused
treatment.

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