Journal Pre-proof

Management of Inflammatory Neurologic and Psychiatric

Manifestations of Systemic Lupus Erythematosus: A Systematic
Review

D.A. Papachristos , S. Oon , J.G. Hanly , M. Nikpour

PII: S0049-0172(20)30285-7
DOI: https://doi.org/10.1016/j.semarthrit.2020.12.004
Reference: YSARH 51746

To appear in: Seminars in Arthritis & Rheumatism

Please cite this article as: D.A. Papachristos , S. Oon , J.G. Hanly , M. Nikpour , Man-
agement of Inflammatory Neurologic and Psychiatric Manifestations of Systemic Lupus
Erythematosus: A Systematic Review, Seminars in Arthritis & Rheumatism (2020), doi:
https://doi.org/10.1016/j.semarthrit.2020.12.004

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.

© 2020 Published by Elsevier Inc.

Management of Inflammatory Neurologic and Psychiatric Manifestations of Systemic
Lupus Erythematosus: A Systematic Review

D.A. Papachristos1, S. Oon1,2,3, J.G. Hanly4, M. Nikpour1,2

1
Department of Rheumatology, St. Vincent’s Hospital, Melbourne, Australia
2
Department of Medicine, The University of Melbourne, Australia
3
Department of Rheumatology, The Royal Melbourne Hospital, Australia
4
Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth
II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia, Canada.

Corresponding author:
A/Prof Mandana Nikpour, The University of Melbourne at St Vincent’s Hospital, 41 Victoria Parade,
Fitzroy VIC 3065, m.nikpour@unimelb.edu.au

Author contributions:
D.A. Papachristos: Conceptualisation, Data curation, Writing – original draft, Writing – review and
editing. S. Oon: Conceptualisation, Data curation, Writing – review and editing. JG Hanly: Data
curation, Writing – review and editing M. Nikpour: Conceptualisation, Data curation, Writing –
review and editing.

1
Abstract
Background: The neurological and psychiatric manifestations of systemic lupus
erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical
presentation and significant morbidity and mortality.
Objectives: Our aim was to comprehensively assess and present the evidence for treatments
used in the management of inflammatory NPSLE.
Methods: Medline, Embase, CINHAL and Cochrane CENTRAL were searched from 1990 to
end of March 2019 using key words that related to NPSLE and treatment. Included studies
comprised clinical trials, observational studies or case series with 5 patients and sufficient
data related to treatment and outcome in NPSLE patients.
Results: There were 7222 studies identified in the search, of which 90 were included in the
review. There was a notable paucity of clinical trials, with only two randomised controlled
trials and one pilot study. Treatment categories included corticosteroids (14 studies),
cyclophosphamide (18 studies), synthetic DMARDs (7 studies), biologic therapies (14
studies), therapeutic plasma exchange (6 studies), intravenous immunoglobulin (2 studies),
autologous stem cell transplant (3 studies), other therapies (8 studies), combination
therapies (6 studies), studies with grouped outcome data (5 studies) and observational
studies with therapy-specific associations (7 studies). Corticosteroids are accepted as first
line treatment in NPSLE and there is low-moderate evidence supporting their benefit.
Moderate evidence, based on consistent data in numerous studies and some trial data,
supports the use of cyclophosphamide in the treatment of NPSLE. Limited data support
some synthetic DMARDs such as mycophenolate, azathioprine and intrathecal
methotrexate. In refractory disease, low-moderate evidence supports rituximab therapy
and limited evidence supports benefit following autologous stem cell transplant. Regarding
adjuvant treatments, limited evidence favours addition of plasma exchange, intravenous
immunoglobulin and hydroxychloroquine. There exists very limited data for other therapies.
Conclusion: There are multiple therapeutic options for the management of inflammatory
NPSLE including systemic, biologic and interventional therapies; however, currently there is
a paucity of high-quality trial data to guide firm recommendations. In order to better
understand the optimal treatment of NPSLE and its different subtypes, further well-
designed clinical trials are needed.

2
Key words: Neuropsychiatric lupus, Immunosuppressive treatments, Neurology, Disease
modifying agents, Biologic therapies

1. Introduction
Systemic Lupus Erythematosus (SLE) is a chronic multi-system autoimmune disease that has
a variable clinical presentation and typically follows a fluctuating and unpredictable disease
course. It can affect multiple organ systems, but the most commonly involved include
mucocutaneous, musculoskeletal, renal, serosal and haematological. The neurological and
psychiatric manifestations of systemic lupus erythematosus (NPSLE) encompass a
heterogeneous group of conditions, whose clinical presentation is also highly variable and
whose pathogenesis is complex [1]. Generally speaking, pathogenic mechanisms fall into
either immune/inflammatory or thrombotic/ischaemic categories and nineteen distinct
syndromes have been previously defined by the American College of Rheumatology (ACR);
these are presented in table 1 [2]. Syndromes range from frequent neurological conditions
such as mild cognitive deficit, headache and mood disorder, to less common manifestations
with high morbidity and mortality including psychosis, seizure, stroke and myelitis. Despite
wide variability between individual studies in a meta-analysis involving 5057 SLE patients,
the prevalence of NP manifestations varied from 17.6 to 44.5% in retrospective and
prospective studies, respectively [3]. An additional challenge is the determination of
attribution of NP events to SLE itself or an alternative cause. Using attribution models
based upon clinical evaluation and clinically indicated investigations studies suggest that 30
to 40% of all NP events in SLE are attributable to SLE [4, 5].

There are many challenges associated with diagnosis and treatment of NPSLE. Not only is
there a lack of accurate diagnostic investigations, but standardised outcome measures do
not exist, making design of studies in NPSLE difficult. Unfortunately there is a relative
paucity of high-quality evidence regarding NPSLE treatment, with very few randomised
controlled trials (RCTs) examining these patients. Likely reasons for this include the
aforementioned protean manifestations of NPSLE (precluding a homogeneous study
population), the difficulties pertaining to accurate objective diagnosis and standardised
measures of outcome, the diversity of immunosuppressive drugs available, and the
historical exclusion of NPSLE patients from RCTs due to concerns about excess morbidity

3
and mortality associated with the disease [6]. Hence, the current data pertaining to
treatment are derived mostly from small, non-controlled studies and case series. Moreover,
to date, there exists no comprehensive review of the literature regarding NPSLE treatment.

This study aims to systematically review the available evidence for therapies used in the
treatment of inflammatory neurologic and psychiatric manifestations of SLE. Studies
examining thrombotic manifestations without a significant inflammatory component, such
as isolated stroke due to antiphospholipid syndrome treated with anticoagulation alone,
were not included in this study. Where possible, appraisal of treatments within different
NPSLE subtypes has been performed.

2. Methods
A systematic search of the literature from January 1990 to March 2019 was performed using
the following databases: MEDLINE, EMBASE, CINAHL and Cochrane. Key search terms
included ‘systemic lupus erythematosus’, ‘neurologic’, ‘neuropsychiatric’, ‘central nervous
system (CNS)’, ‘peripheral nervous system (PNS)’, ‘mental disorders’, ‘therapy’ and
‘treatment’, as well as synonyms and abbreviations thereof (NPSLE, CNS, PNS). Each
manifestation of neurologic and psychiatric SLE was also included in key words, as well as a
comprehensive list of potential treatment options, including corticosteroids, disease
modifying agents and biologic therapies. Anticoagulant therapy was not included as a
distinct treatment modality, because the review focused on immunosuppressive therapies
in NPSLE. However, any use of anticoagulation therapy alongside immunosuppression was
presented as adjunctive treatment. The search was limited to reports in human adults (18
years old) and to articles written in English. Additional articles were sought through hand-
searching of relevant journals, as well as examining the references of key articles (see
appendix A for full search terms).

Two reviewers (DP and SO) independently screened the titles and abstracts of all studies
retrieved by database searches for relevance. If consensus was not reached, a third
reviewer was consulted (MN) regarding the study’s inclusion. One reviewer (DP)
subsequently assessed all articles in their entirety, for eligibility. If included, data were
extracted and tabulated for the review. Articles were grouped by treatment modality.

4
2.1. Inclusion/exclusion criteria
All studies that examined the treatment of inflammatory NPSLE were included in the review,
providing there were at least five cases reported. A manifestation was considered to be
inflammatory if its aetiology was based primarily on autoimmune-mediated inflammation,
or if the institution of any immunosuppressive therapy was necessary. For example, a case
of multifocal strokes secondary to vasculitis of the central nervous system was considered
to represent inflammatory NPSLE, whereas a case of multiple strokes secondary to isolated
antiphospholipid syndrome managed solely with anticoagulation was not. If a therapy was
deemed novel but not reported in a case series of >5 patients, single case reports and
smaller series were included.

2.2. Population
Patients with one or multiple manifestations of neurologic and psychiatric systemic lupus
erythematosus.

2.3. Intervention
This study focused on therapies for inflammatory NPSLE, including systemic, interventional
and biologic therapies. Psychological therapies and psychiatric medications were not
evaluated in this review, due to the difficulty in separating the treatment effect of these
therapies from that of immunosuppression administered. Treatment for non-inflammatory
thrombotic NPSLE was not included.

2.4. Comparator/control
No specific comparison or control group was required for inclusion in the study.

2.5. Outcomes
Primary outcomes:
Clear reporting of clinical outcomes for patients receiving treatment was required for all
studies to be included in the analysis. Articles with insufficient data regarding outcome were
excluded. Since validated outcome measures are not available for NPSLE, most studies used
clinician-reported outcomes to assess clinical response, or judgement-based Likert scales [7,

5
8]. For studies that utilised a general measure of disease activity for lupus, the most
frequently utilised were the British Isles Lupus Assessment Group (BILAG) and the Systemic
Lupus Erythematosus National Assessment (SELENA)-Systemic Lupus Erythematosus Disease
Activity Index (SLEDAI). The BILAG index scores disease activity in SLE across eight different
organ systems, using a series of questions for each system. It incorporates change in disease
state over time and can also can detect partial response. The neuropsychiatric component
incorporates seventeen of the nineteen NPSLE syndromes (according to ACR nomenclature),
excluding anxiety disorder and mood disorder. Conversely, the SELENA-SLEDAI only includes
seven NPSLE syndromes – namely seizure, psychosis, organic brain syndrome, visual
disturbance, cranial nerve disorder, lupus headache and cerebrovascular disease. These are
scored 8 points each if present, but unlike the BILAG index, a partial response cannot be
detected. Some studies included scoring systems for specific manifestations, such as the
American Spinal Injury Association (ASIA) scale and the European Database for Multiple
Sclerosis (EDMUS) grading scale for neuromyelitis optica and myelitis. The response
measure used for each individual study is described in supplementary appendix C.
Response to treatment for each study has been presented in summary tables 2-12. Overall
response (%) is shown as the proportion of patients who achieved a response according to
the measure used in that study (this includes both partial and complete responses). Where
available, the breakdown of partial and complete responses was also described.

Secondary outcomes:
Data regarding adverse events of treatment were also collected (see appendix C for detailed
results).

2.6. Specific exclusions

Studies examining posterior reversible encephalopathy syndrome (PRES) in patients with
SLE were excluded. Although this neurologic condition has been increasingly recognised in
association with SLE, it has not yet been well-defined in this context, and hence was not
included as a manifestation.
Studies involving patients with thrombotic stroke secondary to antiphospholipid syndrome,
who received standard therapy with anticoagulation but without immunosuppression, were

6
excluded. Anticoagulation is a well-established therapy for antiphospholipid syndrome and
the current review focused on immunosuppressive therapies in NPSLE.
One randomised controlled trial by Denburg et al. [9] examining effects of corticosteroids on
cognition and mood in ten patients with mild to moderately active lupus, was not included
in the study for the following reasons: 1. patients with severe NPSLE manifestations had
been excluded from this study, 2. only three of the ten patients reported any neurological
manifestation at enrolment and 3. manifestations were mild (mood swings, depressed
mood and memory difficulties) and these symptoms are common in the general population,
yet no investigations (such as imaging or lumbar puncture) were required to ensure that
symptoms were attributable to SLE.
Two separately published studies reported on the same set of patients and had the same
outcome data [10, 11]. The study with lesser detail regarding patient outcomes was
excluded from the review [11].

2.7. Statistical analysis. Due to the wide variety of study designs, participants, interventions
and outcome measures, a meta-analysis was not performed. Instead, results of studies were
presented in tables and evaluated descriptively.

2.8. Risk of bias assessment

All studies with a comparison group were assessed for risk of bias using the revised
Cochrane risk-of-bias tool for randomised trials (RoB 2), which stratifies risk based on a fixed
set of domains relating to study design, conduct and reporting. All studies without
comparison groups were deemed at high risk of bias overall. All risk of bias assessments
were performed by one reviewer (DP) and subsequently reviewed by a second reviewer
(SO). Please refer to supplementary appendix B for risk of bias assessments.

3. Results
A total of 7222 studies were identified. Of these, 2312 duplicates were removed and 4813
were excluded for reasons described in Figure 1. Of the remaining 97, another 29 were
excluded after full-text review. Hand-searching of relevant journals and review of reference
lists from key articles procured another 22 articles. Ninety studies were finally included in

7
the review. The majority of studies were case series (44 studies) and observational studies
(30 studies), with only 2 randomised controlled trials and one pilot study.

Studies were categorised according to treatments utilised. In total, eleven treatment

categories involving a total of 2230 NPSLE patients were examined (see summary Table 13).
Treatment categories included corticosteroids (14 studies; Table 2) [12-25],
cyclophosphamide (18 studies; Table 3) [8, 26-42], synthetic DMARDs (7 studies; Table 4) [7,
10, 43-47], biologic therapies (14 studies, Table 5) [48-61], plasma exchange (6 studies,
Table 6) [62-67], intravenous immunoglobulin (2 studies, Table 7) [68, 69], autologous stem
cell transplant (3 studies, Table 8) [70-72], novel therapies (8 studies, Table 9) [73, 74],
combination therapies (6 studies, Table 10) [75-80], studies with grouped outcome data for
multiple therapy types (5 studies, Table 11) [81-85] and observational studies not directly
examining response to therapy, but identifying associations between therapies and disease
outcomes (7 studies, Table 12) [86-92].

3.1. Corticosteroids
Fourteen studies examined corticosteroid treatment in 199 patients with NPSLE. There were
two non-controlled trials [12, 13], two observational studies [14, 15] and ten case series
(Table 2) [16-25]. Eight studies reported on a specific neuropsychiatric manifestation:
myelitis (4 studies) [15, 17, 19, 24], optic neuritis (2 studies) [16, 21], cranial neuropathy (1
study) [22] and chorea (1 study) [23], whilst 6 studies included more than one manifestation
[12-14, 18, 20, 25]. Risk of bias was deemed high in all studies. Interventions included
intravenous methylprednisolone (IVMP) in five studies [12, 13, 16, 20, 21], oral
corticosteroids (PO CS) in five [14, 15, 18, 22, 23], oral corticosteroids followed by
sequential azathioprine in one study [25], a mixture of intravenous (IV) and/or oral
corticosteroids in two studies [17, 19] and various IV corticosteroids (IVMP, IV
hydrocortisone, IV dexamethasone) in one study [24]. No study had a comparator group.
All but two studies showed positive results, albeit with varying degrees of response.

3.1.1. Intravenous methylprednisolone (IVMP)

Five studies examined intravenous methylprednisolone (IVMP), with doses ranging from
500mg to 1000mg per day for up to five days. Two small, non-controlled trials observed

8
imaging outcomes using 99mtechnetium-hexamethyl-propylenamine oxime (Tc-HMPAO)
single-photon enhanced computer tomography (SPECT) and 99mTc-ethylcysteinate dimer (Tc-
ECD)-SPECT [12, 13] following IVMP. Both studies reported complete clinical response (CR)
in all patients and complete imaging response in 13/15 (86.7%) and 10/12 (83.3%) patients
respectively. These studies had a very short duration of follow-up – one week in the first
study and two weeks in the second study.
Three case series investigating IVMP in NPSLE reported responses in 62.5% to 100% of
patients. Two examined SLE-related optic neuritis [16, 21] with 62.5% of patients (5/8
patients) [16] and 83% of patients (5/6 patients) achieving a response [21]. In one study,
early initiation of treatment (within 10 days) was associated with improved clinical
outcomes (p<0.025) [16]. Both series showed high relapse occurrence (3/5 and 5/5
patients).

3.1.2. Various intravenous or oral corticosteroids (IV/PO CS)

One observational study investigated treatment with high dose oral corticosteroids
(equivalent to 1mg/kg/d) [14] for various manifestations of NPSLE. Clinical outcomes (if
reported) were positive in the majority of cases: seizures (CR 34/38; 89.5%), psychosis
(13/13; 100%), acute confusional state (11/11; 100%), ‘abnormal conscious state’ (6/6;
100%), myelitis (5/6; 83.3%). Outcomes were not reported for mononeuritis multiplex (3
patients), peripheral neuropathy (2 patients), stroke (2 patients) and aseptic meningitis (2
patients).
One case-control study and three case series examined corticosteroids for the treatment of
SLE-related myelitis [15, 17, 19, 24]. The case control study investigated “high dose oral
corticosteroids” (dose and type of corticosteroid was not specified) in 14 cases of SLE-
myelitis and 37 controls (idiopathic myelitis). Response was seen in only 4/14 SLE-myelitis
patients (28.6%), and 17/37 (46%) controls. Three of the patients also received either
plasma exchange or IV cyclophosphamide, but authors did not specify to whom these
therapies were administered. A similarly low proportion of responders (28.6%, 2/7 patients)
was observed in a case series examining IV or oral CS (variable dose and type, see appendix
C for details) in SLE-myelitis [19]. In this study, early treatment (within 10 days) and IV
rather than oral corticosteroids showed better responses.

9
In contrast, two SLE-myelitis case series showed improvements in all patients receiving
either IV or oral CS [17, 24], with 6/14 complete and 8/14 partial responses (PRs). Two
patients additionally received cyclophosphamide however. Relapses were frequent in both
studies (3/5 and 5/9 respectively).
Oral corticosteroids for neuro-ophthalmological manifestations of SLE were examined in
two case series [18, 22]. Dose was not specified in one study [18] and varied between 30mg
and 1mg/kg in the other [22]. All patients improved, with complete response seen in 3/8
and 5/6 patients, respectively. However, two of the five complete responders in the latter
series additionally received IV cyclophosphamide [22].
Two further case series examined oral corticosteroids (doses not specified) in NPSLE, both
with a moderate proportion of responders (60%). One series examined patients with SLE-
related chorea [23] and the other examined elderly patients with late-onset NPSLE. The
latter study used oral corticosteroids with or without sequential azathioprine [25].
Adverse effects were not detailed in any of these studies.

3.2. Cyclophosphamide
Eighteen studies examined cyclophosphamide (CYC) in 352 patients with NPSLE (Table 3) [8,
26-33, 35-42]. These included two randomised controlled trials (RCT) [26, 28], one pilot
study [27], four non-controlled trials [29-32], three observational studies [8, 33, 34] and
eight case series [35-42]. Ten studies examined a single neuropsychiatric manifestation:
myelitis (six studies) [34, 37, 38, 40-42], optic neuritis (one study) [31], organic brain
syndrome (one study) [39], cerebral venous sinus thrombosis (one study) [33] and psychosis
(one study) [30], whilst seven studies included various manifestations [8, 26, 27, 29, 32, 35,
36]. One study did not specify patients’ neurologic manifestations [28]. Seventeen studies
were deemed at high risk of bias and one study showed ‘some concerns’ in relation to
outcome measurement and selection of reported result (see appendix B). Intravenous (IV)
CYC was the formulation of choice in all but one study, which examined oral CYC followed
by sequential azathioprine [30]. A standard dose IV cyclophosphamide regimen (0.75-1g/m2
monthly or equivalent) was used in six studies [8, 26, 29, 31, 32, 38], a low dose regimen
(200-400mg monthly, 250-500mg/m2 monthly, or 500mg weekly for 3 weeks followed by
500mg monthly) in four [27, 35, 36, 39], a high dose regimen (50mg/kg/d for 4 days) in one
[28] and the dose was not specified in five studies [33, 34, 37, 41, 42]. Three studies had

10
comparison groups, with interventions including IVMP [26], oral prednisolone [27] and high
dose IV CYC [93].
All but one study showed positive results in the majority of patients.
One RCT and one pilot study showed superiority of IV CYC to corticosteroid therapy used
alone [26, 27]. The RCT compared IV CYC (0.75g/m2 of body surface area monthly for one
year, then three-monthly for one year) to IVMP (1g monthly for four months, then two-
monthly for six months and three-monthly for one year) after induction treatment with
IVMP 1g for three days in 32 patients with various NPSLE manifestations. Clinical response
was assessed at four months and was seen in 95% and 46% respectively, with only one
treatment failure in the IV CYC group compared to 7 treatment failures in the IVMP group (p
< 0.001). There were no significant differences in adverse events between groups during 24
months of follow up. Early withdrawal from treatment occurred in two patients in the IVMP
group due to adverse events (pancreatitis and uncontrolled hypertension) compared with
no patients in the IV CYC group. The pilot study compared low dose IV CYC to oral
prednisone in 60 patients with NPSLE. Response was seen in 62.2% of patients receiving IV
CYC versus 21.7% receiving prednisone (p = 0.005) and there were fewer relapses in the IV
CYC group (37.8% versus 78.3%; p = 0.005) [27]. Two herpes zoster infections occurred in
the IV CYC group. One RCT involving 51 patients, 14 of whom had NPSLE, compared high
dose IV cyclophosphamide with standard dose IV cyclophosphamide [28]. For the NPSLE
subgroup, there was no difference between treatment arms, with most patients achieving a
complete response in both groups (standard dose: CR 5/7, high dose: CR 6/7). The two non-
responders in the standard dose group achieved complete response after crossover into the
high dose group. There was no difference in adverse events between groups.
Four non-controlled trials examined cyclophosphamide in NPSLE and showed clinical
response in 80 to 100% of patients [29-32]. One trial investigated oral cyclophosphamide
followed by sequential azathioprine in 13 patients with psychosis. Improvement was seen in
all patients, albeit with one relapse [30]. Another trial examined 10 patients with refractory
optic neuritis (refractory to corticosteroids and/or immunosuppressive agents for at least
two months) showing response in 80% of patients after IV cyclophosphamide [31].
Three observational studies examining IV CYC in NPSLE showed clinical response in most
patients (76.5%, 84% and 100%) [8, 33, 34]. One of these studies examined patients with

11
SLE-related myelitis. All patients in this study responded, with mostly partial responses
achieved (CR 2/15, PR 13/15) [34].
Five case series examined IV CYC in SLE-related myelitis. Results were mixed. One series
included nine patients who received IV CYC with or without plasma exchange (4 patients)
and showed improvement in only 25% [38]. Conversely, a large series of 20 patients with
SLE-myelitis who received either combination IVMP/IV CYC or IVMP alone, showed
improvement in 85% of patients (CR in 25% and PR in 60%) [37]. Although not statistically
significant, the multivariate analysis showed a trend towards unfavourable neurological
outcomes for IVMP used alone (OR 0.08, 95% CI 0.006 – 1.2; p = 0.065). Three additional
case series examining IV CYC in SLE-myelitis showed positive response in between 60-75%
patients, with mostly partial responses [40-42].
Two case series examined low dose IV CYC in patients with various manifestations of NPSLE.
One showed a clinical response in 96% (CR 68%, PR 28%) [36], and the second showed
response in 61% (19/31). Eight patients in the latter study also received plasma exchange.
One case series examined IV cyclophosphamide in ten patients with organic brain syndrome
and reported complete response in 80% of patients, with one relapse [39].
Adverse effects of cyclophosphamide were observed in all studies, particularly infections.
Infections occasionally resulted in the cessation of treatment and sometimes death (five
studies) [8, 33-35, 42]. Other common adverse events included cytopaenias, alopecia,
nausea/vomiting, mild haemorrhagic cystitis and occasionally premature ovarian failure.

3.3. Synthetic DMARDs

Seven studies examined synthetic disease modifying agents in 183 patients with NPSLE
(Table 4) [7, 10, 43-47]. There was one post-hoc analysis of a randomised controlled trial
[43], four observational studies [7, 44, 45, 47] and two case series [10, 46]. Four studies
examined patients with various NPSLE manifestations [7, 10, 44, 47], one study examined a
single manifestation (central nervous system vasculitis) [45] and two studies did not specify
neuropsychiatric manifestations [43, 46]. All studies were deemed at high risk of bias.
Synthetic disease modifying agents included mycophenolate mofetil (four studies) [7, 43-
45], cyclosporin (one study) [46] and intrathecal methotrexate (two studies) [10, 47].

3.3.1. Mycophenolate

12
A post-hoc analysis of a randomised controlled trial in 370 patients with lupus nephritis
examined non-renal disease activity following mycophenolate mofetil versus IV
cyclophosphamide. This included eight patients with significant neurologic involvement
(baseline neurologic BILAG A or B) [43]. Three patients received mycophenolate and five
received cyclophosphamide. All patients improved, hence there was no difference between
groups. However, there was one neuropsychiatric flare by BILAG definition and two flares by
SELENA-SLEDAI definition in the cyclophosphamide group, compared with no flares in the
mycophenolate group.
Two observational studies examining mycophenolate in patients with mixed manifestations
of NPSLE showed response in 77.8% and 96.15% of patients respectively. In the latter study,
the very high proportion of responders (96.15%) by the end of follow up had risen from
53.22% at three months [7]. The authors note that “IVIG and/or rituximab were used in
refractory cases”, yet further details regarding these therapies or to how many patients they
were administered are not reported.
A third observational study examined 16 lupus patients with central nervous system
vasculitis who received mycophenolate as either initial (7 patients), secondary (after
relapse, 3 patients) or maintenance (5 patients) therapy [45]. Clinical response, or
maintenance thereof, was achieved in 86.7% of patients.
Adverse events for mycophenolate were generally mild. However, one severe leukopaenia
was noted and one severe infection resulting in death [7].

3.3.2. Azathioprine
No study examined azathioprine primarily for the treatment of NPSLE, but this medication
was utilised commonly [16, 17, 34, 48, 50, 57, 63, 75-78]. Most often, it was used in
combination with other immunosuppressive agents, such as cyclophosphamide [34] and
rituximab [30, 48, 50], hence the treatment effect of azathioprine could not be separated
from these other therapies. However, four studies that examined various therapies for the
management of NPSLE (Table 11) did describe outcomes separately for patients who
received azathioprine. One study examined patients with lupus-related peripheral
neuropathy, of whom 16 received azathioprine and 19 received cyclophosphamide. A
similar rate of remission was seen for those receiving azathioprine (93.8%) as for those
receiving IV cyclophosphamide induction (94.4%, p = 1) [82]. Another study examined

13
patients with various manifestations of NPSLE, 10 of whom received azathioprine. All but
one responded to treatment [81]. A myelitis study included three patients receiving
azathioprine alongside corticosteroids; all patients achieved a partial response [83]. Finally,
a case series examining lupus psychosis included three patients treated with azathioprine
and corticosteroids, two of whom achieved a partial response with ongoing chronic
psychosis, and one of whom had a complete response. Azathioprine has been used as a
sequential or maintenance therapy in three studies, with moderate to high proportions of
patients maintaining clinical response [25, 30, 80].

3.3.3. Cyclosporin
One case series examined cyclosporin as either initial or maintenance therapy in 40 patients
with SLE, 11 of whom had neurologic involvement [46]. Cyclosporin was used as initial
therapy for ‘moderate’ disease and as maintenance therapy for ‘severe’ disease after
administration of IV CYC. Outcomes were not reported for NPSLE patients separately, only
for total study numbers (87.5% response overall with 57.5% ‘excellent’ response, 30%
‘good/fair’ response). However, only two ‘unsatisfactory outcomes’ were observed in the
entire study and these were both NPSLE patients receiving cyclosporin for maintenance
treatment. Adverse events were mild and did not require drug cessation.

3.3.4. Intrathecal methotrexate

Two observational studies examined intrathecal methotrexate and dexamethasone in
patients with various manifestations of NPSLE and reported high response figures (88.9%
and 91.7%) [10, 47]. The latter study should be interpreted with caution, as a number of
patients (details were not provided in the study) also received cyclophosphamide and
intravenous immune globulin [10]. Adverse events were only specified in one study, but
included three transient neurological events: dysaestheisa of the lower limbs, headache and
sphincter incontinence [10].

3.4. Biologic therapies

Fourteen studies investigated biologic therapies in 166 patients with NPSLE (Table 5) [48-
61]. Twelve studies examined rituximab [48-59] and two examined belimumab [60, 61].
Study types included a post-hoc analysis of two randomised controlled trials [60], three non-

14
controlled trials [48-50], six observational studies [51-55, 61] and four case series [56-59].
Seven studies included patients with various manifestations of NPSLE [48-51, 53, 56, 60],
one study examined SLE-myelitis [58], and six studies did not specify neurological
manifestations [52, 54, 55, 57, 59, 61]. All studies were deemed at high risk of bias.

3.4.1. Anti-CD20 Therapy

Twelve studies examined the anti-CD20 monoclonal antibody rituximab [48-59]. Dosing
regimens most commonly used were 1000mg intravenously two weeks apart or 375mg/m2
intravenously weekly for 2-4 weeks [48-57, 59]. Three studies used a regimen of 500mg
intravenously weekly for 2-4 weeks [49, 51, 58]. All studies used concurrent corticosteroids
(IV or oral) and all but one study [58] included patients refractory to established therapies
such as corticosteroids, immunosuppressive agents (including cyclophosphamide), IVIG and
therapeutic plasma exchange (TPE). All studies showed positive results, with overall clinical
response ranging from 73-100% of patients. Relapse after rituximab was not always
documented, but when documented, was widely variable from 8% to 80%. Response to re-
treatment with rituximab was successful in all patients for whom this was reported. One
study that utilised two rituximab regimens – 1000mg two weeks apart and 375mg/m2
weekly for 4 weeks – showed a fivefold higher infection rate with the latter regimen [54].
Adverse events were generally mild (infusion reactions, mild infections). Three studies
reported severe serum sickness reactions [56, 57, 59] and two reported deaths from serious
infections [54, 55].

3.4.2. Anti-B-cell Activating Factor (BAFF) Therapy

Two studies, one of which analysed two trials, investigated belimumab [60, 61], a human
IgG1λ monoclonal antibody that inhibits B-cell survival by neutralising soluble B lymphocyte
stimulator. Dosing regimens included belimumab 10mg/kg intravenously and 1mg/kg
intravenously, administered on days 0, 14, 28 and every 28 days thereafter. A post-hoc
analysis of the BLISS-52 and BLISS-76 trials described outcomes after belimumab for various
organ system domains including neurologic domains [60]. Of note, patients with severe
NPSLE were excluded from these trials, so numbers analysed in this study are small and
manifestations mild. Overall, analyses of BILAG and SELENA-SLEDAI changes for the CNS
cohort were highly variable and limited by the small sample size (5% of the study cohort)

15
and lack of correction for multiple comparisons. The largest difference between belimumab
and placebo for CNS domains was seen in a subgroup analysis of patients who had high
serological activity at baseline. In patients with high serological activity and CNS
involvement (N = 13), two thirds (66.7%) achieved SELENA-SLEDAI improvements in the
belimumab groups, compared to none receiving placebo. However, due to small numbers
this was not statistically significant. Headache was the only manifestation for which
outcomes were reported separately: improvements were seen in 69.2% of patients
receiving 10mg/kg, 100% of patients receiving 1mg/kg and 20% of patients receiving
placebo. Again, the small numbers (N = 24) did not allow further conclusions to be drawn.
An observational study examined belimumab 10mg/kg in 195 SLE patients, 9 of whom had
NPSLE [61]. No response to belimumab was seen in NPSLE patients. Furthermore, four
patients without NPSLE at baseline developed NPSLE manifestations (1 stroke, 1 psychosis, 1
depressive episode and 1 seizure) while taking belimumab, and two patients with NPSLE at
baseline had worsening of their disease.
Adverse events were either mild [61] or not reported [60].

3.5. Therapeutic plasma exchange (TPE)

Six studies examined TPE in 73 patients with NPSLE (Table 6) [62-64, 66, 67]. Five studies
included various manifestations of NPSLE and one did not specify NPSLE manifestations
[65]. There was one non-controlled trial [62], one observational study [63] and four case
series [64-67]. All studies were deemed at high risk of bias.
In most studies, TPE was administered 2-3 times weekly for 3-4 weeks then as per
participants’ symptomatology. In all studies, concurrent therapies were utilised, including
corticosteroids, cytotoxic agents, synthetic disease modifying agents and in some cases
rituximab. The proportion of patients with response after TPE was high, ranging from 74-
100%; however, all patients received additional therapies (most commonly
cyclophosphamide in 5/6 studies), leaving the true benefit of TPE difficult to interpret. One
study noted that improvement/stabilisation of symptoms occurred in most cases during the
first week of TPE commencement [63]. Another study found that those who achieved
complete response had a shorter time between first cyclophosphamide pulse and
commencement of TPE than those who had a partial response (0.6 vs. 3.6 weeks
respectively) [64].

16
In only one study was TPE used without cyclophosphamide [67]. This was a case series of
five NPSLE patients receiving TPE alongside corticosteroids (doses between 10-100mg/d). All
patients responded to therapy.
Adverse events associated with TPE were infrequent but included bleeding at catheter site,
transient hypotension, catheter infections or clots, mild arrhythmias and electrolyte
abnormalities. One study reported pneumothorax and haemothorax [63].

3.6. Intravenous Immunoglobulin

Two studies examined intravenous immunoglobulin (IVIG) in 17 patients with NPSLE (Table
7) [68, 69]. One study included various manifestations [68], while another examined SLE-
related chronic inflammatory demyelinating polyneuropathy (CIDP) [69]. Both were case
series and both were at high risk of bias. Dosing regimens used were: 400mg/kg per day
over 5 days repeated monthly (at least one course) and 2g/kg per day over 5 days repeated
monthly (2 courses). The series with various NPSLE manifestations showed clinical
responses to IVIG in 73% of neurologic patients, half of whom achieved complete responses
[68]. For SLE-CIDP, a ‘good response’ (defined as a more than 50% improvement in
symptoms) after IVIG was seen in only 3/6 patients (50%), two of whom also received TPE
[69]. Adverse events were either mild [68] or not reported [69].

3.7. Autologous stem cell transplant

Three studies examined autologous stem cell transplant (auto-SCT) in 59 patients with
NPSLE (Table 8). There was one non-controlled trial [70] and two observational studies [71,
72]. All patients were refractory to corticosteroids and at least one immunosuppressive
agent (most frequently cyclophosphamide). One study included patients with various
manifestations of NPSLE [70] and two studies did not specify NPSLE manifestations [71, 72].
All studies were at high risk of bias.
Treatment protocols involved mobilisation using IV CYC (2-4g/m2) with granulocyte-colony
stimulating factor (G-CSF) 5g/kg/d, or IV CYC alone, or G-CSF alone. Conditioning regimens
included IV CYC (50mg/kg daily for 4 days) with anti-thymocyte globulin (ATG: 30mg/kg/d
for 3 days), or various combinations of IV CYC, busulphan, etoposide, fludarabine,
melphalan, thiotepa, alemtuzumab and BEAM (carmustine, etoposide, cytarabine,
melphalan). Response after auto-SCT was favourable overall; however, only one study

17
reported responses for neurologic patients separately [71]. In this study, the frequency of
CNS manifestations declined over time. At mobilisation, frequency of CNS manifestations
was 46%; this decreased to approximately 5% after six months (exact value not displayed on
graph) and was approximately 10% at 24 months. Of note, one patient developed CNS
involvement following auto-SCT.
One non-controlled trial [70] and one observational study [72] examined auto-SCT in SLE,
including some patients with manifestations of NPSLE. Outcomes were described for the
entire cohort (NPSLE outcomes were not reported separately). Five-year survival after auto-
SCT was high in both studies (84% and 81%), however the probability of disease-free
survival at 5 years was only 50% and 29%. The latter study showed a relapse incidence of
56% [72].
Adverse events were common in all studies (reported for overall study numbers). Infections,
cytokine storm following ATG, and new immune events (such as immune
thrombocytopaenia, autoimmune haemolytic anaemia and acquired haemophilia) were
most common. Post-transplant lymphoproliferative disorder occurred in two patients [71,
72] and death related to auto-SCT occurred in 1 [70], 7 [71] and 4 patients [72].

3.8. Other therapies

Eight studies involving 12 patients investigated other therapies for the treatment of NPSLE
(Table 9) [73, 74, 94-99]. Interventions included electro-convulsive therapy (ECT) [73, 74],
immunoablative IV cyclophosphamide [94], immunoadsorption therapy [95], tacrolimus
[96], cerebrospinal fluid pheresis [97, 98] and iloprost [99]. There were three case series [73,
74, 95] and five case reports. All studies were deemed at high risk of bias. Two case series
showed improvement after electroconvulsive therapy in 6 patients with psychosis. In one
series, three patients had refractory psychosis and catatonia despite 1-6 months of IVMP
plus IV CYC therapy [73]. All had significant clinical improvement according to the Bush-
Francis Catatonia Rating Scale after the third (2 patients) or fourth (1 patient) ECT sessions.
The second series showed similar results: clinical improvement occurred in three patients
with psychosis and mood disorder after the 1st, 3rd and 5th ECT sessions. However, patients
in the latter study had received treatment with IV corticosteroids and IV cyclophosphamide
10-22 days prior. The only adverse event reported was mild headache post ECT.

18
One study examined an immunoablative dose of IV CYC in a patient with SLE-related
neuromyelitis optica after failure of multiple therapies including IVMP, mycophenolate,
tacrolimus, oral CYC, standard dose IV CYC, IVIG and rituximab. A dose of 2g per day was
given for 4 days along with G-CSF. The patient had clinical improvement (measured by visual
acuity, limb power and ability to walk with aids) and radiological improvement (marked
reduction in hyperintense spinal cord signals), followed by no relapse over 18 months
despite no maintenance immunosuppression. However, rituximab had been given three
months prior to immunoablative IV CYC, potentially confounding results. The patient
experienced alopecia and gastrointestinal upset.
One case series examined selective immunoadsorption of immunoglobulins
(immunoglobulin apheresis) with low dose IVIG in 5 SLE patients, one of whom had NPSLE
(seizures). This patient achieved a complete response but also received high dose
prednisolone and 2 doses of IV CYC (800mg and 1000mg one week apart).
One case report described clinical and radiological improvement of SLE-related CNS
vasculitis after treatment with tacrolimus. However, IVMP was administered concurrently
and clinical improvement was seen after the second IVMP pulse. It should be mentioned
that the patient’s first presentation of CNS vasculitis responded to oral prednisone.
Two studies showed positive clinical outcomes after cerebrospinal fluid pheresis in two
patients with NPSLE. Regimens included: 1. Two filtration sessions three days apart, 225mL
filtered per session, and 2. Five filtration sessions over five days, 400ml CSF filtered per
session, followed by a 5-day break then another 6 sessions. Both cases received IVMP and IV
CYC 1-3 weeks prior to CSF pheresis.
One case report described improvement of SLE-related cognitive dysfunction following
iloprost [99]. The NPSLE diagnosis had been made on neuropsychological testing, as well as
brain perfusion imaging (SPECT scan). Iloprost was given for the management of Raynaud
phenomenon at a dose of 1.5ng/kg/min every 6h/d for 10 days. The patient experienced
complete reversal of cognitive dysfunction, confirmed on neuropsychological testing. SPECT
scan also normalised.

3.9. Combination therapies

Six studies involving 281 patients used multiple different combinations of drugs for the
treatment of NPSLE (Table 10) [75-80]. There were two observational studies [75, 76] and

19
four case series [77-80]. One study included patients with various NPSLE manifestations [75]
and five studies focused on particular manifestations: myelitis (two studies) [76, 77],
psychosis (one study) [78], seizures (one study) [79] and demyelinating syndrome (one
study) [80]. Risk of bias was high in all studies.
Treatment combinations were numerous (see Table 10), but all included corticosteroids
accompanied by two or more of the following additional therapies: cyclophosphamide, a
synthetic DMARD, IVIG or TPE. Combination therapies yielded mostly positive results. One
observational study examining patients with severe neuropsychiatric involvement showed
response in 74% of patients, half of whom received combinations. In this study,
combinations involving rituximab, IVIG and TPE most commonly achieved improvement.
Four case series examining specific manifestations (psychosis, seizures, demyelinating
syndrome and a myelitis case series) used combination therapies in approximately half of
patients, showing at least partial clinical responses in all cases. In contrast, one case-control
study examining SLE-related myelitis showed poor responses in patients receiving
combination therapy, with only 2/5 achieving a ‘good outcome’ [76].
Adverse events were either not reported [76, 79, 80] or events were typical for medication
types, for example, combinations with cyclophosphamide resulted in adverse events such as
infection, cytopaenias and amenorrhoea. One study recorded corticosteroid side effects
including Cushing’s syndrome, myopathy and osteopaenia [75]. Death from serious
infections occurred in two studies [77, 78].

3.10. Studies with grouped outcome data for multiple therapy types
Five studies involving 115 patients utilised various therapies for the treatment of NPSLE,
with outcomes reported for only some therapies or for the overall cohort (Table 11) [81-85].
There were three observational studies [81-83] and two case series [84, 85]. One study
examined various NPSLE manifestations [81] and four studies were selective for a
neuropsychiatric manifestation: myelitis (2 studies) [83, 84], peripheral neuropathy (1 study)
[82] and mononeuritis multiplex (1 study) [85]. Risk of bias was high in all studies. Overall
clinical response was high in all studies, with improvement (at least partial response) in 75-
100% of patients. One observational study documented response for three drugs
separately: cyclophosphamide, 4/9 responses (all with minor resulting disability),
azathioprine, 9/10 responses (2 with CR, 5 with minor resulting disability and 2 with

20
moderate disability) and TPE, 1/2 responses (moderate resulting disability) [81]. Two case
series examining SLE-related myelitis found that most favourable responses occurred with
either combination IVMP/CYC or IVMP alone [83, 84]. One of these series noted that all
responses occurred within 7 days of treatment with high dose corticosteroids [83]. Both
studies showed relapse to be more common in patients receiving corticosteroids alone. One
observational study examining various therapies for SLE-related peripheral neuropathy
showed a high overall response (92%), as did a case series examining different therapies for
SLE-related mononeuritis multiplex (70%) [85].
Adverse events were either not reported [81, 85] or most commonly due to infections in
patients receiving cyclophosphamide [82-84], with death in two cases [82, 84].

3.11. Observational studies with therapy-specific associations

Seven observational studies involving 755 patients with neuropsychiatric involvement found
associations between particular therapies and disease outcome (Table 12) [86-92]. Four
studies included various manifestations of NPSLE [86, 90-92], while three focused on
seizures [87-89]. Medications for which associations were identified included anti-platelet
therapy (one study) [86], antimalarial medications (five studies) [87-89, 91], corticosteroids
(two studies) [90, 92] and cyclophosphamide (one study) [91]. One observational study
showed that antiplatelet therapy was associated with reduced mortality risk in patients with
NPSLE (HR 0.22, 95% CI 0.07–0.74) and this was seen not only in patients with stroke (HR
0.17, 95% CI 0.04–0.75) but also in patients without stroke (HR 0.48, 95% CI 0.06–3.60).
Three studies examining SLE-related seizures showed benefits associated with antimalarial
use: in one study, hydroxychloroquine use was associated with a longer time to seizure
occurrence (HR 0.35, 95% CI 0.15–0.80, p=0.0131) [87]; in another study, prior use of
antimalarial medication in the absence of immunosuppressive agents was associated with a
reduced risk of seizures (HR 0.7, 95% CI 0.01–0.66) [89] and a third study showed that
antimalarial medications were associated with low incidences of neurological involvement
(OR 0.61, 95% CI 0.40–0.92, p = 0.02) [88]. Two observational studies involving patients with
various NPSLE manifestations showed that 1. Hydroxychloroquine use was associated with a
longer time to NP damage (HR = 0.58; 95% CI, 0.36–0.93) [90] and 2. Previous
hydroxychloroquine use was negatively associated with development of NPSLE (RR 0.5, p =
0.02) [91]. One of these studies also showed that moderate dose (10-30mg) prednisone was

21
associated with a longer time to NP damage (HR = 0.56; 95% CI 0.35–0.92). Another study
showed that previous cyclophosphamide use was positively associated with the
development of NPSLE (RR 4.3, p <0.001). One observational study showed that IVMP was
an independent predictor of NP damage [92]. Many of the above associations are
confounded by the fact that SLE patients with severe disease are more likely to develop
NPSLE and also more likely to have received treatment with high dose corticosteroids or
cyclophosphamide. Equally, patients with mild SLE are less likely to develop NPSLE and more
likely to have received treatment with hydroxychloroquine.

4. Discussion
This review summarises the available evidence regarding treatments used in the
management of inflammatory neurological and psychiatric systemic lupus erythematosus
(NPSLE). The pathophysiology of NPSLE remains poorly understood, but in general,
neuroinflammation and cerebral ischaemia are accepted as the two major contributing
mechanisms in NPSLE [100]. This review focuses on manifestations that reflect an
inflammatory aetiology and hence studies examining purely thrombotic manifestations,
namely stroke secondary to antiphospholipid syndrome alone, are not included.

The existing literature surrounding disease management in NPSLE comprises predominantly

narrative reviews [101-116], with a handful of systematic reviews that focus on either a
particular neuropsychiatric manifestation [117-119] or a particular drug within a wider lupus
cohort [120-124]. One Cochrane review has addressed the topic of treatment in NPSLE
[125], but owing to the aforementioned lack of high-quality evidence, only one study was
included in that review. To our knowledge, our systematic review is the first to
comprehensively summarise and present all treatment data for inflammatory NPSLE.

Ninety studies were analysed in total, with only two available randomised controlled trials
and one pilot study, highlighting the relative paucity of high-quality data in this area of lupus
disease management. The remaining studies comprised case series, observational studies,
and small, open-label, non-controlled trials. Studies were extremely heterogeneous in their
patient population, study design, treatment protocol and outcome measures; therefore,
data were analysed qualitatively rather than quantitatively.

22
It should be mentioned that current treatment paradigms for NPSLE involve multiple
treatment modalities, naturally complicating the assessment of efficacy for individual
therapies. Nevertheless, based on the collected and reviewed data, we have identified a
number of therapeutic strategies for the management of neurologic and psychiatric
manifestations of SLE with an immune or inflammatory aetiology. These are summarised in
Figure 2.

Corticosteroids play a key role in the acute treatment of most manifestations of lupus.
Reflecting this, all studies utilised corticosteroids for NPSLE, either alone or in combination
with other therapies. Of twelve studies where corticosteroids were the principal therapy,
ten had positive results. Most studies were case series and small open-label non-controlled
trials, conferring a high risk of publication bias due to the tendency to overreport efficacy.
Nevertheless, based on consistent results in a large number of studies, there is low-
moderate evidence to support the use of corticosteroid therapy in NPSLE management [12-
14, 16-18, 20-25]. Furthermore, early treatment (within 10 days of symptoms onset), as well
as intravenous formulations, were associated with better outcomes in numerous studies
[16, 19, 83]. Relapse after treatment with corticosteroids was common, particularly for the
manifestations of optic neuritis [16, 21] and lupus myelopathy [17, 19, 24].
We recommend that the initial management of inflammatory NPSLE include the early
institution of corticosteroids followed by consideration of a second immunosuppressive
agent. For severe disease, we suggest IV methylprednisolone, 1g daily for three days,
followed by oral corticosteroid taper. For mild to moderate disease, oral corticosteroids may
be employed at doses that are dependent on severity, anywhere between 20mg/day and
1mg/kg/day. Close monitoring for the adverse effects of corticosteroids is essential,
especially when using high-dose regimens. Side effects of high dose corticosteroids can
include acute psychosis and mood disturbance, which may further complicate the
management of NPSLE.

Regarding concomitant therapy, moderate evidence supports the use of cyclophosphamide

in the treatment of NPSLE [8, 26-37, 39-42]. This is based on consistent positive results from
numerous studies (sixteen of seventeen), including two randomised trials that showed

23
superiority of IV CYC to corticosteroid therapy used alone [26, 27]. Limited data also support
favourable outcomes for low dose cyclophosphamide regimens in NPSLE [27, 35, 36, 39].
Regarding subgroup data for different manifestations of NPSLE, there is limited evidence to
support the use of cyclophosphamide in the treatment of lupus myelitis [34, 37, 40-42, 76,
77, 94]; however, the proportion of responders is similar to that seen in studies using IV
corticosteroids alone for this condition. Since all patients managed with cyclophosphamide
also received concurrent IV corticosteroids, it is difficult to separate the treatment effect of
cyclophosphamide from that of IV corticosteroids. Hence, the interference of concomitant
therapies is a confounding factor. Regarding optic neuritis, limited data support the use of
cyclophosphamide for refractory disease [31], in line with results from a systematic review
examining neuro-ophthalmological manifestations of SLE [117]. For psychosis, limited data
also support benefit with cyclophosphamide therapy, both oral and IV formulations [30, 78].
Very limited evidence (single case series) exists for cyclophosphamide use in other NPSLE
manifestations, such as organic brain syndrome [39], seizures [79] and lupus-related venous
sinus thrombosis [33].

In terms of DMARD therapy, limited evidence favours benefit for mycophenolate in NPSLE
[7, 43-45]. A post-hoc analysis of a randomised controlled trial comparing mycophenolate
with IV cyclophosphamide showed no difference in response between groups, although
NPSLE numbers were very small (N = 8) [43]. Only one study examined mycophenolate in a
specific NPSLE manifestation – lupus-related CNS vasculitis – and showed favourable results
for acute and maintenance treatment [45]. Regarding azathioprine, there was limited data
supporting its use in acute [78, 81-83] and maintenance management of NPSLE [25, 30].
Favourable results for specific manifestations were seen in two studies, examining lupus-
related peripheral neuropathy [82] and psychosis [30]. The data examining intrathecal
methotrexate and dexamethasone in NPSLE are confounded by concurrent administration
of other systemic therapies including IV corticosteroids and IV cyclophosphamide in both
studies [10, 33]. Furthermore, intrathecal therapy is relatively invasive and has the potential
for neurological complications; hence, we suggest it should be reserved for refractory
disease. Data regarding cyclosporin therapy in NPSLE are conflicting [46, 62]. Despite
positive results in one study [62], the treatment effect of cyclosporin alone cannot be
interpreted due to simultaneous treatment with cyclophosphamide and TPE in all patients.

24
Another study examining cyclosporin in 40 SLE patients (11 with NPSLE) noted two
‘unsatisfactory outcomes’ within the entire cohort, both in NPSLE patients [46].
Based on the available evidence, we recommend either azathioprine or mycophenolate
alongside corticosteroids in mild to moderate NPSLE.

With regards to biologic therapies, low-moderate evidence supports the use of rituximab in
NPSLE [48-59], particularly in refractory disease. This is based on consistent results from
numerous non-controlled studies (12 studies) and is in keeping with the wider literature, in
which five systematic reviews describe positive effects of rituximab for the treatment of
various lupus manifestations [120-124], including one systematic review that specifically
examines rituximab for refractory NPSLE [123]. A number of auto-antibodies including anti-
N-methyl-D-aspartate receptor antibodies, anti-phospholipid antibodies and anti-ribosomal
P antibodies are purported to have pathogenic roles in NPSLE [126-129], which might
explain the efficacy of treatments that target B cell depletion. However, presence of these
autoantibodies in SLE patients does not always correlate with neuropsychiatric involvement
[130, 131] and the role of B cells and autoantibodies in NPSLE remains incompletely
understood [132, 133]. In our review, relapse rates after treatment with rituximab varied
widely (8-80%), but the available data regarding those who did relapse showed high
response figures after retreatment [53, 58, 59]. Limited evidence from subgroup data
supports the use of rituximab in lupus myelitis [53, 58]. We recommend that rituximab
should be used alongside corticosteroids in severe or refractory cases of NPSLE.
Data regarding belimumab were conflicting. Although analysis of the BLISS trials [60]
showed a trend towards benefit in NPSLE patients with high serological activity and also in
patients with headache, both trials originally excluded patients with severe NPSLE, and
positive findings were based on very small numbers of patients with milder features.
Another study found no benefit using belimumab in NPSLE patients, and also saw the
development of NPSLE after study commencement in four patients taking belimumab [61].
Targeting other cytokines for NPSLE may be effective. For example, interferon has been
shown to play a potential role in NPSLE in pre-clinical studies [134]; however, the effect of
agents targeting this pathway such as anifrolumab, an anti-interferon-receptor monoclonal
antibody, which recently met its primary endpoint in a phase 3 clinical trial [135], remains to
be studied in NPSLE.

25
In patients with severe NPSLE, limited data support the use of TPE in conjunction with other
therapies [62-67], the caveat being that IV cyclophosphamide was used in all but one study.
Several studies examining adjunctive TPE in lupus nephritis have shown no additional
benefit of TPE over standard of care [136-141]. As the current treatment paradigms for
NPSLE are based on the treatment of other severe organ manifestations of SLE such as
nephritis, this suggests that adjunctive TPE may also not be of any additional value in the
treatment of NPSLE. Limited data support the use of adjunctive IVIG in NPSLE management
[68, 75]. In patients with refractory disease, there is limited evidence showing favourable
outcomes with autologous stem cell transplant [70-72].

Novel therapies with positive case report data include ECT for lupus psychosis [73, 74],
immunoablative dose IV CYC for refractory lupus myelitis [94], immunoadsorption therapy
for lupus-related seizures [95], tacrolimus for stroke secondary to central nervous system
vasculitis [96], cerebrospinal fluid pheresis for stroke secondary to central nervous system
vasculitis and for demyelinating syndrome [97, 98] and iloprost for severe cognitive
dysfunction [99]. Seven out of eight of these reports were confounded by the simultaneous
or recent use of other therapies including cyclophosphamide and rituximab. The only report
in which no other therapy was used was the report describing iloprost in a patient with
severe cognitive dysfunction [99]. There is not yet enough evidence to recommend use of
any of the above therapies.

Studies including combination therapies showed mostly positive results, but there is
insufficient data to draw specific conclusions about the benefit of adding a third agent to
corticosteroid therapy with one other immunosuppressive agent.

In terms of ‘other therapies’, observational data suggest a role for both hydroxychloroquine
and anti-platelet therapy in the general management of NPSLE. Regarding anti-platelet
therapy, beneficial effect was described even in the absence of stroke as the primary
manifestation of NPSLE [86]. Five observational studies found associations between
antimalarial therapy and lower rates of neurological involvement or damage [87-91],
including three studies examining predominantly seizures [87-89]. Although such

26
associations may be biased by therapy indication, i.e. patients with lower disease activity
are likely to be managed with hydroxychloroquine, we would nevertheless recommend the
addition of hydroxychloroquine in all patients with NPSLE.
Anticoagulation was used in select patients alongside immunosuppression in thirteen
studies [8, 33, 37, 38, 41, 42, 63, 64, 70, 75, 77, 81, 83]. Indications for anticoagulation
included a history of anti-phospholipid syndrome, new antiphospholipid syndrome as part
of the inflammatory presentation, or occasionally, the presence of antiphospholipid
antibodies without thrombosis. The latter indication occurred only in studies examining
lupus myelitis, and this was likely due to the previously proposed pathogenic mechanism of
possible thrombosis secondary to antiphospholipid antibodies [142]. Five of the myelitis
studies [37, 38, 42, 77, 83] contained sufficient data to examine outcomes of patients with
antiphospholipid antibodies (without thrombosis) who were treated with anticoagulation,
compared to those who did not receive anticoagulation, and there were no obvious
differences regarding myelitis outcomes. This is consistent with findings of a systematic
review exploring the value of checking antiphospholipid antibodies in lupus myelitis, in
which anticoagulation was not found to have any additional therapeutic effect in patients
with myelitis and positive antiphospholipid antibodies [119].
We therefore recommend the addition of therapeutic anticoagulation only in patients with
documented antiphospholipid syndrome.

Other adjunctive therapies used in the treatment of NPSLE include anticonvulsants,

antidepressants and anti-psychotics. However, treatment effects of these medications could
not be separated from concomitant immunomodulatory therapy and therefore, we suggest
that such therapies may be used at the discretion of the treating physician for concomitant
symptomatic effect.

This review has a number of limitations. Firstly, of the ninety available studies, only two are
randomised controlled trials. The scarcity of trial data is due to multiple issues relating to
trial design in a NPSLE patient population. First of all, the multitude of NPSLE manifestations
along with their rarity and variable presentation makes recruitment of a homogeneous
study population difficult. Secondly, there remains a lack of accurate diagnostic tests and
standardised measures to easily document outcomes and thirdly, the high morbidity and

27
mortality shown to be associated with NPSLE raises ethical issues when randomising
patients to particular treatments, or to a defined study protocol. For this reason, NPSLE
patients are often excluded from randomised studies. One solution to this problem would
be to design trials that compare the current standard of care with new treatments (in
addition to standard of care therapy). Unfortunately, the standard of care for patients with
severe NPSLE often comprises multiple potent therapies including cyclophosphamide,
rituximab and adjuvant therapeutic plasma exchange, leaving any treatment effect of an
additional therapy difficult to perceive, and substantially increasing risks associated with
severe immunosuppression. For this reason, most available studies examining NPSLE
therapy are either case series or observational studies; this is reflected in our review.
Furthermore, case series inherently confer a high risk of publication bias, because successful
cases are more likely to be reported in the literature, leading to efficacy overreporting. All
but one study in this review were deemed at high risk of bias, and only 5 studies had
comparator groups. Many of the included observational studies were limited by their
retrospective design, small sample size, or inclusion of only a small subset of NPSLE patients
within a larger cohort.
Another major limitation of this review relates to the heterogeneity of studies with regards
to design, patient population, treatment protocol and also outcome measures. Diverse
patient populations cannot easily be compared between studies and moreover, grouped
results of mixed patient populations do not accurately reflect treatment effect for a
particular manifestation. The vast majority of studies in this review grouped
neuropsychiatric manifestations together and hence, subgroup analysis of different
manifestations was extremely limited. Due to the paucity of metrics for NPSLE disease
severity and outcome, most studies did not use validated instruments. Instead, arbitrary
definitions for response were frequently used, or subjective physician-reported outcomes.
These kinds of descriptive data are difficult to compare across studies. Furthermore, those
studies that did utilise validated outcome measures of disease activity, such as the BILAG,
SLEDAI and SELENA-SLEDAI, were nevertheless limited as these instruments do not capture
all neuropsychiatric manifestations. No instrument currently exists which adequately
measures disease activity and outcomes for all neuropsychiatric manifestations, and this will
be a vital development for better study of NPSLE in future. A study by Hanly et al. has shown
that changes in patient-derived SF-36 summary and subscale scores are strongly associated

28
with clinical outcomes in NPSLE, and hence this could be a reliable outcome measure for
future studies [143].
Finally, some studies had missing data, while others attributed treatment success to one
therapy despite a combination of therapies being used. In such studies, it was not possible
to separate the treatment effect of one drug from another, and hence results were
inconclusive.

The major strength of this review is that it comprehensively and systematically describes all
the immunomodulatory treatments used in inflammatory neurological and psychiatric
manifestations of systemic lupus erythematosus. Additionally, we have presented levels of
evidence for each treatment described, to help guide the treating physician and hopefully
aid in the development of a treatment algorithm for NPSLE in the future.

5. Conclusion
In a systematic review focussing on the management of inflammatory NPSLE, we have
identified many potential treatment options including systemic, biologic and interventional
therapies. However, the numerous limitations as discussed above preclude firm
recommendations regarding treatment from being made. Nevertheless, we have suggested
a management approach based on the current available evidence. In order to better tailor
treatment to NPSLE patients in future, an improved understanding of the pathophysiology
of the disease is necessary, as well as validated measures that accurately assess the severity
of each manifestation and its response to treatment. Ultimately, well-designed randomised
controlled trials that examine a homogeneous population of NPSLE patients (i.e. a single
manifestation) should analyse a new therapy in comparison to the current standard of care.

29
Acknowledgements:
MN holds a National Health and Medical Research Council of Australia Investigator Grant
(GNT 1176538).

Funding:
This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.

Conflict of Interest Statement:

None of the authors have any conflicts of interest pertaining to this work.

References:
1. Schwartz, N., A.D. Stock, and C. Putterman, Neuropsychiatric lupus: new mechanistic
insights and future treatment directions. Nat Rev Rheumatol, 2019. 15(3): p. 137-
152.
2. The American College of Rheumatology nomenclature and case definitions for
neuropsychiatric lupus syndromes. Arthritis Rheum, 1999. 42(4): p. 599-608.
3. Unterman, A., et al., Neuropsychiatric syndromes in systemic lupus erythematosus: a
meta-analysis. Semin Arthritis Rheum, 2011. 41(1): p. 1-11.
4. Hanly, J.G., et al., Short-term outcome of neuropsychiatric events in systemic lupus
erythematosus upon enrollment into an international inception cohort study.
Arthritis Rheum, 2008. 59(5): p. 721-9.
5. Bortoluzzi, A., et al., Development and validation of a new algorithm for attribution
of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford),
2015. 54(5): p. 891-8.
6. Hanly, J.G., et al., Neuropsychiatric events in systemic lupus erythematosus: a
longitudinal analysis of outcomes in an international inception cohort using a
multistate model approach. Ann Rheum Dis, 2020. 79(3): p. 356-362.
7. Gupta, N., et al., Mycophenolate mofetil and deflazacort combination in
neuropsychiatric lupus: a decade of experience from a tertiary care teaching hospital
in southern India. Clin Rheumatol, 2017. 36(10): p. 2273-2279.
8. Fanouriakis, A., et al., Cyclophosphamide in combination with glucocorticoids for
severe neuropsychiatric systemic lupus erythematosus: a retrospective, observational
two-centre study. Lupus, 2016. 25(6): p. 627-36.
9. Denburg, S.D., R.M. Carbotte, and J.A. Denburg, Corticosteroids and
neuropsychological functioning in patients with systemic lupus erythematosus.
Arthritis Rheum, 1994. 37(9): p. 1311-20.
10. Dong, Y., et al., Intrathecal injection with methotrexate plus dexamethasone in the
treatment of central nervous system involvement in systemic lupus erythematosus.
Chin Med J (Engl), 2001. 114(7): p. 764-6.

30
11. Zhang, X., et al., [Central nervous system involvement in systemic lupus
erythematosus]. Zhonghua Nei Ke Za Zhi, 1999. 38(10): p. 681-4.
12. Sun, S.S., et al., Evaluation of the effects of methylprednisolone pulse therapy in
patients with systemic lupus erythematosus with brain involvement by Tc-99m
HMPAO brain SPECT. Eur Radiol, 2004. 14(7): p. 1311-5.
13. Liu, F.Y., et al., Usefulness of Tc-99m ECD brain SPECT to evaluate the effects of
methylprednisolone pulse therapy in lupus erythematosus with brain involvement: a
preliminary report. Rheumatol Int, 2003. 23(4): p. 182-5.
14. Kasitanon, N., et al., Neuropsychiatric manifestations in Thai patients with systemic
lupus erythematosus. Asian Pac J Allergy Immunol, 2002. 20(3): p. 179-85.
15. Schulz, S.W., et al., Initial presentation of acute transverse myelitis in systemic lupus
erythematosus: demographics, diagnosis, management and comparison to idiopathic
cases. Rheumatol Int, 2012. 32(9): p. 2623-7.
16. Lin, Y.C., A.G. Wang, and M.Y. Yen, Systemic lupus erythematosus-associated optic
neuritis: clinical experience and literature review. Acta Ophthalmol, 2009. 87(2): p.
204-10.
17. Chan, K.F. and M.L. Boey, Transverse myelopathy in SLE: clinical features and
functional outcomes. Lupus, 1996. 5(4): p. 294-9.
18. Teoh, S.C., E.Y. Yap, and K.G. Au Eong, Neuro-ophthalmological manifestations of
systemic lupus erythematosus in Asian patients. Clin Exp Ophthalmol, 2001. 29(4): p.
213-6.
19. Harisdangkul, V., D. Doorenbos, and S.H. Subramony, Lupus transverse myelopathy:
better outcome with early recognition and aggressive high-dose intravenous
corticosteroid pulse treatment. J Neurol, 1995. 242(5): p. 326-31.
20. Bell, C.L., et al., Magnetic resonance imaging of central nervous system lesions in
patients with lupus erythematosus. Correlation with clinical remission and
antineurofilament and anticardiolipin antibody titers. Arthritis Rheum, 1991. 34(4):
p. 432-41.
21. Siatkowski, R.M., et al., Optic neuropathy and chiasmopathy in the diagnosis of
systemic lupus erythematosus. J Neuroophthalmol, 2001. 21(3): p. 193-8.
22. Genevay, S., et al., Oculomotor palsy in six patients with systemic lupus
erythematosus. A possible role of antiphospholipid syndrome. Lupus, 2002. 11(5): p.
313-6.
23. Reiner, P., et al., Long-term outcome of 32 patients with chorea and systemic lupus
erythematosus or antiphospholipid antibodies. Mov Disord, 2011. 26(13): p. 2422-7.
24. Salmaggi, A., et al., Spinal cord involvement and systemic lupus erythematosus:
clinical and magnetic resonance findings in 5 patients. Clin Exp Rheumatol, 1994.
12(4): p. 389-94.
25. Dennis, M.S., et al., Neuropsychiatric systemic lupus erythematosus in elderly people:
a case series. J Neurol Neurosurg Psychiatry, 1992. 55(12): p. 1157-61.
26. Barile-Fabris, L., et al., Controlled clinical trial of IV cyclophosphamide versus IV
methylprednisolone in severe neurological manifestations in systemic lupus
erythematosus. Ann Rheum Dis, 2005. 64(4): p. 620-5.
27. Stojanovich, L., et al., Neuropsychiatric lupus favourable response to low dose i.v.
cyclophosphamide and prednisolone (pilot study). Lupus, 2003. 12(1): p. 3-7.

31
28. Petri, M., et al., High-dose cyclophosphamide versus monthly intravenous
cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial.
Arthritis Rheum, 2010. 62(5): p. 1487-93.
29. Malaviya, A.N., et al., Intermittent intravenous pulse cyclophosphamide treatment in
systemic lupus erythematosus. Indian J Med Res, 1992. 96: p. 101-8.
30. Mok, C.C., C.S. Lau, and R.W. Wong, Treatment of lupus psychosis with oral
cyclophosphamide followed by azathioprine maintenance: an open-label study. Am J
Med, 2003. 115(1): p. 59-62.
31. Galindo-Rodríguez, G., et al., Cyclophosphamide pulse therapy in optic neuritis due to
systemic lupus erythematosus: an open trial. Am J Med, 1999. 106(1): p. 65-9.
32. Boumpas, D.T., et al., Pulse cyclophosphamide for severe neuropsychiatric lupus. Q J
Med, 1991. 81(296): p. 975-84.
33. Wang, L., et al., Clinical Characteristics of Cerebral Venous Sinus Thrombosis in
Patients with Systemic Lupus Erythematosus: A Single-Centre Experience in China. J
Immunol Res, 2015. 2015: p. 540738.
34. Quintanilla-González, L., et al., Myelitis in systemic lupus erythematosus: clinical
characteristics and effect in accrual damage. A single-center experience. Lupus, 2017.
26(3): p. 248-254.
35. Neuwelt, C.M., et al., Role of intravenous cyclophosphamide in the treatment of
severe neuropsychiatric systemic lupus erythematosus. Am J Med, 1995. 98(1): p. 32-
41.
36. Ramos, P.C., et al., Pulse cyclophosphamide in the treatment of neuropsychiatric
systemic lupus erythematosus. Clin Exp Rheumatol, 1996. 14(3): p. 295-9.
37. Saison, J., et al., Systemic lupus erythematosus-associated acute transverse myelitis:
manifestations, treatments, outcomes, and prognostic factors in 20 patients. Lupus,
2015. 24(1): p. 74-81.
38. Kovacs, B., et al., Transverse myelopathy in systemic lupus erythematosus: an
analysis of 14 cases and review of the literature. Ann Rheum Dis, 2000. 59(2): p. 120-
4.
39. Martin-Suarez, I., et al., Immunosuppressive treatment in severe connective tissue
diseases: effects of low dose intravenous cyclophosphamide. Ann Rheum Dis, 1997.
56(8): p. 481-7.
40. Barile, L. and C. Lavalle, Transverse myelitis in systemic lupus erythematosus--the
effect of IV pulse methylprednisolone and cyclophosphamide. J Rheumatol, 1992.
19(3): p. 370-2.
41. Téllez-Zenteno, J.F., et al., Longitudinal myelitis associated with systemic lupus
erythematosus: clinical features and magnetic resonance imaging of six cases. Lupus,
2001. 10(12): p. 851-6.
42. Hryb, J.P., et al., Myelitis in systemic lupus erythematosus: clinical features,
immunological profile and magnetic resonance imaging of five cases. Spinal Cord Ser
Cases, 2016. 2: p. 16005.
43. Ginzler, E.M., et al., Nonrenal disease activity following mycophenolate mofetil or
intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in
a multicenter, prospective, randomized, open-label, parallel-group clinical trial.
Arthritis Rheum, 2010. 62(1): p. 211-21.

32
44. Tselios, K., et al., Mycophenolate Mofetil in Nonrenal Manifestations of Systemic
Lupus Erythematosus: An Observational Cohort Study. J Rheumatol, 2016. 43(3): p.
552-8.
45. Salvarani, C., et al., Mycophenolate mofetil in primary central nervous system
vasculitis. Semin Arthritis Rheum, 2015. 45(1): p. 55-9.
46. Germano, V., et al., Cyclosporine A in the long-term management of systemic lupus
erythematosus. J Biol Regul Homeost Agents, 2011. 25(3): p. 397-403.
47. Wang, J., et al., Impact analysis of autoantibody level and NR2 antibody level in
neuropsychiatric SLE treated by methylprednisolone combined with MTX and DXM
intrathecal injection. Cell Biochem Biophys, 2014. 70(2): p. 1005-9.
48. Tokunaga, M., et al., Efficacy of rituximab (anti-CD20) for refractory systemic lupus
erythematosus involving the central nervous system. Ann Rheum Dis, 2007. 66(4): p.
470-5.
49. Tanaka, Y., et al., A multicenter phase I/II trial of rituximab for refractory systemic
lupus erythematosus. Mod Rheumatol, 2007. 17(3): p. 191-7.
50. Tokunaga, M., et al., Down-regulation of CD40 and CD80 on B cells in patients with
life-threatening systemic lupus erythematosus after successful treatment with
rituximab. Rheumatology (Oxford), 2005. 44(2): p. 176-82.
51. Iwata, S., et al., Efficacy and safety of anti-CD20 antibody rituximab for patients with
refractory systemic lupus erythematosus. Lupus, 2018. 27(5): p. 802-811.
52. Vital, E.M., et al., B cell biomarkers of rituximab responses in systemic lupus
erythematosus. Arthritis Rheum, 2011. 63(10): p. 3038-47.
53. Pinto, L.F., et al., Rituximab induces a rapid and sustained remission in Colombian
patients with severe and refractory systemic lupus erythematosus. Lupus, 2011.
20(11): p. 1219-26.
54. Fernández-Nebro, A., et al., Multicenter longitudinal study of B-lymphocyte depletion
in refractory systemic lupus erythematosus: the LESIMAB study. Lupus, 2012. 21(10):
p. 1063-76.
55. Ramos-Casals, M., et al., Off-label use of rituximab in 196 patients with severe,
refractory systemic autoimmune diseases. Clin Exp Rheumatol, 2010. 28(4): p. 468-
76.
56. Lu, T.Y., et al., A retrospective seven-year analysis of the use of B cell depletion
therapy in systemic lupus erythematosus at University College London Hospital: the
first fifty patients. Arthritis Rheum, 2009. 61(4): p. 482-7.
57. Smith, K.G., et al., Long-term comparison of rituximab treatment for refractory
systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment.
Arthritis Rheum, 2006. 54(9): p. 2970-82.
58. Ye, Y., et al., Rituximab in the treatment of severe lupus myelopathy. Clin Rheumatol,
2011. 30(7): p. 981-6.
59. Hickman, R.A., et al., The efficacy and safety of rituximab in a chart review study of
15 patients with systemic lupus erythematosus. Clin Rheumatol, 2015. 34(2): p. 263-
71.
60. Manzi, S., et al., Effects of belimumab, a B lymphocyte stimulator-specific inhibitor,
on disease activity across multiple organ domains in patients with systemic lupus
erythematosus: combined results from two phase III trials. Ann Rheum Dis, 2012.
71(11): p. 1833-8.

33
61. Hui-Yuen, J.S., et al., Safety and Efficacy of Belimumab to Treat Systemic Lupus
Erythematosus in Academic Clinical Practices. J Rheumatol, 2015. 42(12): p. 2288-95.
62. Bambauer, R., U. Schwarze, and R. Schiel, Cyclosporin A and therapeutic plasma
exchange in the treatment of severe systemic lupus erythematosus. Artif Organs,
2000. 24(11): p. 852-6.
63. Neuwelt, C.M., The role of plasmapheresis in the treatment of severe central nervous
system neuropsychiatric systemic lupus erythematosus. Ther Apher Dial, 2003. 7(2):
p. 173-82.
64. Bartolucci, P., et al., Adjunctive plasma exchanges to treat neuropsychiatric lupus: a
retrospective study on 10 patients. Lupus, 2007. 16(10): p. 817-22.
65. Aguirre-Valencia, D., et al., Therapeutic Plasma Exchange as Management of
Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases.
Autoimmune Dis, 2019. 2019: p. 5350960.
66. Soyuöz, A., et al., Therapeutic plasma exchange for refractory SLE: A comparison of
outcomes between different sub-phenotypes. Eur J Rheumatol, 2018. 5(1): p. 32-36.
67. Hashimoto, H., et al., Outcome of collagen vascular diseases by treatment with
plasmapheresis. Ther Apher, 1998. 2(4): p. 268-72.
68. Camara, I., et al., Treatment with intravenous immunoglobulins in systemic lupus
erythematosus: a series of 52 patients from a single centre. Clin Exp Rheumatol,
2014. 32(1): p. 41-7.
69. Vina, E.R., et al., Chronic inflammatory demyelinating polyneuropathy in patients
with systemic lupus erythematosus: prognosis and outcome. Semin Arthritis Rheum,
2005. 35(3): p. 175-84.
70. Burt, R.K., et al., Nonmyeloablative hematopoietic stem cell transplantation for
systemic lupus erythematosus. JAMA, 2006. 295(5): p. 527-35.
71. Jayne, D. and A. Tyndall, Autologous stem cell transplantation for systemic lupus
erythematosus. Lupus, 2004. 13(5): p. 359-65.
72. Alchi, B., et al., Autologous haematopoietic stem cell transplantation for systemic
lupus erythematosus: data from the European Group for Blood and Marrow
Transplantation registry. Lupus, 2013. 22(3): p. 245-53.
73. Bica, B.E., et al., Electroconvulsive therapy as a treatment for refractory
neuropsychiatric lupus with catatonia: three case studies and literature review.
Lupus, 2015. 24(12): p. 1327-31.
74. Tan, L.P. and L.E. Tan, Electroconvulsive therapy for severe neuropsychiatric lupus
with psychosis. J ECT, 2013. 29(3): p. 243-6.
75. Bortoluzzi, A., et al., Therapeutic strategies in severe neuropsychiatric systemic lupus
erythematosus: experience from a tertiary referral centre. Reumatismo, 2012. 64(6):
p. 350-9.
76. Lu, X., et al., Prognostic factors of lupus myelopathy. Lupus, 2008. 17(4): p. 323-8.
77. D'Cruz, D.P., et al., Transverse myelitis as the first manifestation of systemic lupus
erythematosus or lupus-like disease: good functional outcome and relevance of
antiphospholipid antibodies. J Rheumatol, 2004. 31(2): p. 280-5.
78. Pego-Reigosa, J.M. and D.A. Isenberg, Psychosis due to systemic lupus
erythematosus: characteristics and long-term outcome of this rare manifestation of
the disease. Rheumatology (Oxford), 2008. 47(10): p. 1498-502.
79. Kampylafka, E.I., et al., Epileptic syndrome in systemic lupus erythematosus and
neuronal autoantibody associations. Lupus, 2016. 25(11): p. 1260-5.

34
80. Chessa, E., et al., Demyelinating syndrome in SLE: review of different disease
subtypes and report of a case series. Reumatismo, 2017. 69(4): p. 175-183.
81. Joseph, F.G., G.A. Lammie, and N.J. Scolding, CNS lupus: a study of 41 patients.
Neurology, 2007. 69(7): p. 644-54.
82. Fargetti, S., et al., Short- and Long-Term Outcome of Systemic Lupus Erythematosus
Peripheral Neuropathy: Bimodal Pattern of Onset and Treatment Response. J Clin
Rheumatol, 2019.
83. Mok, C.C., et al., Acute transverse myelopathy in systemic lupus erythematosus:
clinical presentation, treatment, and outcome. J Rheumatol, 1998. 25(3): p. 467-73.
84. Ahn, S.M., et al., Clinical features and prognoses of acute transverse myelitis in
patients with systemic lupus erythematosus. Korean J Intern Med, 2019. 34(2): p.
442-451.
85. Rivière, E., et al., Clinicopathological features of multiple mononeuropathy
associated with systemic lupus erythematosus: a multicenter study. J Neurol, 2017.
264(6): p. 1218-1226.
86. Zirkzee, E.J., et al., Mortality in neuropsychiatric systemic lupus erythematosus
(NPSLE). Lupus, 2014. 23(1): p. 31-8.
87. Andrade, R.M., et al., Seizures in patients with systemic lupus erythematosus: data
from LUMINA, a multiethnic cohort (LUMINA LIV). Ann Rheum Dis, 2008. 67(6): p.
829-34.
88. Feng, X., et al., Prognostic indicators of hospitalized patients with systemic lupus
erythematosus: a large retrospective multicenter study in China. J Rheumatol, 2011.
38(7): p. 1289-95.
89. Hanly, J.G., et al., Seizure disorders in systemic lupus erythematosus results from an
international, prospective, inception cohort study. Ann Rheum Dis, 2012. 71(9): p.
1502-9.
90. González, L.A., et al., Time to neuropsychiatric damage occurrence in LUMINA (LXVI):
a multi-ethnic lupus cohort. Lupus, 2009. 18(9): p. 822-30.
91. Mok, C.C., C.S. Lau, and R.W. Wong, Neuropsychiatric manifestations and their
clinical associations in southern Chinese patients with systemic lupus erythematosus.
J Rheumatol, 2001. 28(4): p. 766-71.
92. Mok, C.C., C.H. To, and A. Mak, Neuropsychiatric damage in Southern Chinese
patients with systemic lupus erythematosus. Medicine (Baltimore), 2006. 85(4): p.
221-8.
93. Petri, M., Use of hydroxychloroquine to prevent thrombosis in systemic lupus
erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol
Rep, 2011. 13(1): p. 77-80.
94. Mok, C.C., et al., Immunoablative cyclophosphamide for refractory lupus-related
neuromyelitis optica. J Rheumatol, 2008. 35(1): p. 172-4.
95. Graninger, M., et al., Immunoadsorption therapy (therasorb) in patients with severe
lupus erythematosus. Acta Med Austriaca, 2002. 29(1): p. 26-9.
96. Kizu, H., et al., Improvement of irregularity of brain vessel walls in systemic lupus
erythematosus by tacrolimus. Clin Rheumatol, 2011. 30(5): p. 715-8.
97. Pfausler, B., et al., Multimodal therapy in life-threatening cerebral lupus
erythematosus: the benefit of cerebrospinal fluid pheresis. Int Arch Allergy Immunol,
1995. 107(4): p. 592-4.

35
98. Stahl, H.D., et al., Filtration of cerebrospinal fluid for acute demyelinating neuropathy
in systemic lupus erythematosus. Clin Rheumatol, 2000. 19(1): p. 61-3.
99. Mathieu, A., et al., Sustained normalization of cerebral blood-flow after iloprost
therapy in a patient with neuropsychiatric systemic lupus erythematosus. Lupus,
2002. 11(1): p. 52-6.
100. Jeltsch-David, H. and S. Muller, Autoimmunity, neuroinflammation, pathogen load: A
decisive crosstalk in neuropsychiatric SLE. J Autoimmun, 2016. 74: p. 13-26.
101. Hanly, J.G., et al., Review: Nervous System Disease in Systemic Lupus Erythematosus:
Current Status and Future Directions. Arthritis Rheumatol, 2019. 71(1): p. 33-42.
102. Govoni, M., et al., The diagnosis and clinical management of the neuropsychiatric
manifestations of lupus. J Autoimmun, 2016. 74: p. 41-72.
103. Alessi, H., et al., Neuropsychiatric Lupus in clinical practice. Arq Neuropsiquiatr, 2016.
74(12): p. 1021-1030.
104. Magro-Checa, C., et al., Management of Neuropsychiatric Systemic Lupus
Erythematosus: Current Approaches and Future Perspectives. Drugs, 2016. 76(4): p.
459-83.
105. Kivity, S., et al., Pharmacologic management of neuropsychiatric lupus. Expert Rev
Clin Pharmacol, 2016. 9(1): p. 103-8.
106. Hanly, J.G., Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol,
2014. 10(6): p. 338-47.
107. Xiong, W. and R.G. Lahita, Pragmatic approaches to therapy for systemic lupus
erythematosus. Nat Rev Rheumatol, 2014. 10(2): p. 97-107.
108. Postal, M., L.T. Costallat, and S. Appenzeller, Neuropsychiatric manifestations in
systemic lupus erythematosus: epidemiology, pathophysiology and management.
CNS Drugs, 2011. 25(9): p. 721-36.
109. Fong, K.Y. and J. Thumboo, Neuropsychiatric lupus: clinical challenges, brain-reactive
autoantibodies and treatment strategies. Lupus, 2010. 19(12): p. 1399-403.
110. Bertsias, G.K. and D.T. Boumpas, Pathogenesis, diagnosis and management of
neuropsychiatric SLE manifestations. Nat Rev Rheumatol, 2010. 6(6): p. 358-67.
111. Joseph, F.G. and N.J. Scolding, Neurolupus. Pract Neurol, 2010. 10(1): p. 4-15.
112. Hanly, J.G. and M.J. Harrison, Management of neuropsychiatric lupus. Best Pract Res
Clin Rheumatol, 2005. 19(5): p. 799-821.
113. Sanna, G., M.L. Bertolaccini, and A. Mathieu, Central nervous system lupus: a clinical
approach to therapy. Lupus, 2003. 12(12): p. 935-42.
114. Sanna, G., M.L. Bertolaccini, and M.A. Khamashta, Neuropsychiatric involvement in
systemic lupus erythematosus: current therapeutic approach. Curr Pharm Des, 2008.
14(13): p. 1261-9.
115. Hermosillo-Romo, D. and R.L. Brey, Diagnosis and management of patients with
neuropsychiatric systemic lupus erythematosus (NPSLE). Best Pract Res Clin
Rheumatol, 2002. 16(2): p. 229-44.
116. Jafri, K., S.L. Patterson, and C. Lanata, Central Nervous System Manifestations of
Systemic Lupus Erythematosus. Rheum Dis Clin North Am, 2017. 43(4): p. 531-545.
117. Man, B.L., C.C. Mok, and Y.P. Fu, Neuro-ophthalmologic manifestations of systemic
lupus erythematosus: a systematic review. Int J Rheum Dis, 2014. 17(5): p. 494-501.
118. Piga, M., et al., Demyelinating syndrome in SLE encompasses different subtypes: Do
we need new classification criteria? Pooled results from systematic literature review
and monocentric cohort analysis. Autoimmun Rev, 2017. 16(3): p. 244-252.

36
119. Katsiari, C.G., et al., Acute transverse myelitis and antiphospholipid antibodies in
lupus. No evidence for anticoagulation. Eur J Neurol, 2011. 18(4): p. 556-63.
120. Lan, L., F. Han, and J.H. Chen, Efficacy and safety of rituximab therapy for systemic
lupus erythematosus: a systematic review and meta-analysis. J Zhejiang Univ Sci B,
2012. 13(9): p. 731-44.
121. Murray, E. and M. Perry, Off-label use of rituximab in systemic lupus erythematosus:
a systematic review. Clin Rheumatol, 2010. 29(7): p. 707-16.
122. Cobo-Ibáñez, T., et al., Efficacy and safety of rituximab in the treatment of non-renal
systemic lupus erythematosus: a systematic review. Semin Arthritis Rheum, 2014.
44(2): p. 175-85.
123. Narváez, J., et al., Rituximab therapy in refractory neuropsychiatric lupus: current
clinical evidence. Semin Arthritis Rheum, 2011. 41(3): p. 364-72.
124. Ramos-Casals, M., et al., Rituximab in systemic lupus erythematosus: A systematic
review of off-label use in 188 cases. Lupus, 2009. 18(9): p. 767-76.
125. Fernandes Moça Trevisani, V., et al., Cyclophosphamide versus methylprednisolone
for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane
Database Syst Rev, 2013(2): p. CD002265.
126. DeGiorgio, L.A., et al., A subset of lupus anti-DNA antibodies cross-reacts with the
NR2 glutamate receptor in systemic lupus erythematosus. Nat Med, 2001. 7(11): p.
1189-93.
127. Wang, J.Y., et al., Anti-N-Methyl-D-Aspartic Acid Receptor 2 (Anti-NR2) Antibody in
Neuropsychiatric Lupus Serum Damages the Blood-Brain Barrier and Enters the Brain.
Med Sci Monit, 2019. 25: p. 532-539.
128. Katzav, A., et al., Antibody-specific behavioral effects: intracerebroventricular
injection of antiphospholipid antibodies induces hyperactive behavior while anti-
ribosomal-P antibodies induces depression and smell deficits in mice. J
Neuroimmunol, 2014. 272(1-2): p. 10-5.
129. Segovia-Miranda, F., et al., Pathogenicity of lupus anti-ribosomal P antibodies: role of
cross-reacting neuronal surface P antigen in glutamatergic transmission and
plasticity in a mouse model. Arthritis Rheumatol, 2015. 67(6): p. 1598-610.
130. Husebye, E.S., et al., Autoantibodies to a NR2A peptide of the glutamate/NMDA
receptor in sera of patients with systemic lupus erythematosus. Ann Rheum Dis,
2005. 64(8): p. 1210-3.
131. Karassa, F.B., et al., Accuracy of anti-ribosomal P protein antibody testing for the
diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-
analysis. Arthritis Rheum, 2006. 54(1): p. 312-24.
132. Wen, J., et al., The role of B cells and autoantibodies in neuropsychiatric lupus.
Autoimmun Rev, 2016. 15(9): p. 890-5.
133. Wen, J., et al., B cell and/or autoantibody deficiency do not prevent neuropsychiatric
disease in murine systemic lupus erythematosus. J Neuroinflammation, 2016. 13(1):
p. 73.
134. McHugh, J., Systemic lupus erythematosus: IFN drives synapse loss via microglia. Nat
Rev Rheumatol, 2017. 13(8): p. 449.
135. Morand, E.F., et al., Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N
Engl J Med, 2020. 382(3): p. 211-221.

37
136. Lewis, E.J., et al., A controlled trial of plasmapheresis therapy in severe lupus
nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med, 1992.
326(21): p. 1373-9.
137. Danieli, M.G., et al., Synchronised therapy and high-dose cyclophosphamide in
proliferative lupus nephritis. J Clin Apher, 2002. 17(2): p. 72-7.
138. Li, M., et al., Therapeutic effect of double-filtration plasmapheresis combined with
methylprednisolone to treat diffuse proliferative lupus nephritis. J Clin Apher, 2016.
31(4): p. 375-80.
139. Wallace, D.J., et al., Randomized controlled trial of pulse/synchronization
cyclophosphamide/apheresis for proliferative lupus nephritis. J Clin Apher, 1998.
13(4): p. 163-6.
140. Nakamura, T., et al., Comparative effects of plasmapheresis and intravenous
cyclophosphamide on urinary podocyte excretion in patients with proliferative Lupus
nephritis. Clin Nephrol, 2002. 57(2): p. 108-13.
141. Doria, A., et al., Therapy of lupus nephritis. A two-year prospective study. Ann Med
Interne (Paris), 1994. 145(5): p. 307-11.
142. Lavalle, C., et al., Transverse myelitis: a manifestation of systemic lupus
erythematosus strongly associated with antiphospholipid antibodies. J Rheumatol,
1990. 17(1): p. 34-7.
143. Hanly, J.G., et al., SF-36 summary and subscale scores are reliable outcomes of
neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis, 2011.
70(6): p. 961-7.

38
Tables and Figures

Table 1. The American College of Rheumatology Nomenclature and Case Definitions for
Neuropsychiatric Lupus Syndromes
Central Nervous System
Aseptic meningitis
Cerebrovascular disease
Headache (including migraine and benign intracranial hypertension)
Movement disorder (chorea)
Myelopathy
Seizure disorders
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
Peripheral nervous system
Acute inflammatory demyelinating polyradiculoneuropathy
(Guillain-Barre´ syndrome)
Autonomic disorder
Mononeuropathy, single/multiplex
Myasthenia gravis
Neuropathy, cranial
Plexopathy
Polyneuropathy
Arthritis Rheum, 1999. 42(4): p. 599-608

39
Table 2
Corticosteroids (CS)
Population
INTRAVENOUS METHYLPREDNISOLONE (IVMP)
Non-controlled trials
Sun et al. (2004) N = 15
PSY (7), MD (5), COG (5),
SEIZ (4), ACS (4), cerebellar
ataxia (3), ‘impaired
concentration’ (2),
‘dizziness’ (2), H/A (2)
Liu et al. (2003) N = 12
PSY (7), MD (5), ACS (4),
SEIZ (4), Cerebellar ataxia
(3), COG (3), H/A (2)
Case series
Lin et al. (2009) N=8
ON (8)
Bell et al. (1991) N = 7 (with serial MRIs)
SEIZ (4), H/A (3), CVA (2),
ACS (1), COG (1), ANX (1)
Response N (%)/
Intervention Comparator
Risk of bias Assessment
IVMP (15) None Overall response 100%; clinical CR
Dose: 1g/d x 3 then PNL 15/15 (100%); imaging CR 13/15;
2mg/kg/d one week imaging PR 2/15
Risk of bias: high
IVMP (12) None Overall response 100%; clinical CR
Dose: 1g/d x 3 then PNL 12/12 (100%); imaging CR 10/12;
2mg/kg/d one week imaging PR 2/12
Risk of bias: high
IVMP (8) None Overall response 62.5%; CR 4/8
Dose: 1g/d x 3 (50%), PR 1/8 (12.5%), relapse 3/5 of
Concurrent Rx: PNL (8), IV responders
CYC (1), AZA (1), HQL (1)
Risk of bias: high
IVMP (7) None Overall response clinical 100%, MRI
Dose varied: 0.5-1g/d 57%
Concurrent Rx: PO CS CR clinical 4/7 (57%), CR MRI 3/7
(43%)
PR 3/7 (43%), PR MRI 1/7 (14%)
40

Siatkowski et al. (2001) N=6
ON (6)
VARIOUS INTRAVENOUS/ORAL CORTICOSTEROIDS
Observational studies
Kasitanon et al. (2002) N = 91 (NPSLE, 98 events)
SEIZ (38), PSY (13), ACS (11),
‘Abnormal conscious state’
(6), TM (6), MM (3), PN (2),
CVA (2), AM (2)
N = 390 (total study
numbers)
Schulz et al. (2011) N = 14 (received Rx)
TM (14)
Controls N = 39 (idiopathic
TM)
IVMP (6)
Dose: 0.25g q6H x 3-5 days
then weaning PNL
Concurrent Rx:
triamcinolone acetonide IO
injection (1), IV CYC at
relapse (2), AZA at relapse
(1)
High dose CS (91)
Dose: equivalent to
≥1mg/kg/d PNL
Concurrent Rx: CYC (2)
High dose PO CS (14)
Dose and type CS not
specified
Concurrent Rx: IV CYC (2),
TPE (1)
Risk of bias: high
None Overall response 83%; CR 5/6,
relapse 5/5 (100%), >1 relapse 4/5
(80%)
Risk of bias: high
None Response by manifestation:
SEIZ: CR 34/38 (89.5%); relapse 4/34
PSY: 13/13 (100%)
ACS: 11/11 (100%), ‘Abnormal
conscious state’: 6/6 (100%)
TM: 5/6 (83.3%); CR 3/6 (50%), PR
2/6 (33.3%)
Not reported: MM, PN, CVA, AM
Risk of bias: high
None Overall response 4/14 (28.6%) all PR
Note: not clear which of the 14
patients received CYC or TPE
41

Case series
Chan et al. (1996) N = 9 (14 events) IVMP (5 events)
TM (9) Dose: 1g/d x 3
PO CS (PNL, 9 events)
Dose: 0.75-1mg/kg/d
Concurrent Rx: IV CYC (3
events), PO CS (14 events),
AZA (1)
Teoh et al. (2001) N=8 PO CS (8)
MM (1), INO (1), CN (2), ON Dose: not specified
(3), inferior rectus Concurrent Rx: IV CS (1),
myopathy (1) retrobulbar depot steroid
(1)
Harisdangkul et al. N=7 CS IV or PO (7)
(1995) TM (7) Dose varied; see appendix C
for dosing details by case
Concurrent Rx: N/A
Genevay et al. (2002) N=6 PO CS (6)
CN (6) Dose varied; see appendix C
for dosing details by case
Concurrent Rx: IV CYC (2),
ASA (1)
Reiner et al. (2011) N = 6 (NPSLE, adults) PO CS (5)
Chorea (6) Dose and type CS not
Risk of bias: high
None Overall response 100%; CR 3/9
(33%), PR 6/9 (67%), relapse 5/9
(55.5%), response with re-treatment
5/5 (100%)
Risk of bias: high
None Overall response 100%; CR 3/8
(37.5%), PR 5/8 (62.5%), relapse 2/8
(25%)
Risk of bias: high
None Overall response 28.6% (CR 2/7),
stability in 3/7 (42.9%)
Risk of bias: high
None Overall response 6/6 (100%); CR 5/6
(83%), PR 1/6 (16.6%)
Risk of bias: high
None Overall response 3/5 (60%)
42
 N = 32 (total study specified Risk of bias: high
numbers) Concurrent Rx: TPE (2), ASA
(2), anticonvulsants (4)

Salmaggi et al. (1994)
N=5 IV CS (5) None Overall response 100%; CR 3/5
TM (5) Dose varied; see appendix C (60%), PR 2/5 (40%), relapse 3/5
for dosing details by case (60%)
Concurrent Rx: N/A
Risk of bias: high

Dennis et al. (1992)
N = 5 (NPSLE, elderly)
Subacute confusional state
(2), Parkinsonism (2),
Depression (2), CVA (2),
COG (2)
PO CS (PNL) +/- sequential None Overall response 3/5 (60%)
AZA (3)
Dose (PNL) not specified Risk of bias: high
Dose (AZA) varied: 100-
150mg/d
Concurrent Rx: anti-
parkinson Rx (2), ASA (1)

Abbreviations: CS (corticosteroids), N (number), IVMP (intravenous methylprednisolone), PSY (psychosis), MD (mood disorder), COG (cognitive impairment), SEIZ (seizure),
ACS (acute confusional state), H/A (headache), CR (complete response), PR (partial response), ON (optic neuritis), Rx (treatment), PNL (prednisolone), IV (intravenous), CYC
(cyclophosphamide), AZA (azathioprine), HQL (hydroxychloroquine), MRI (magnetic resonance imaging), CVA (cerebrovascular accident), ANX (anxiety), PO (per oral), IO
(intraocular), NPSLE (neuropsychiatric systemic lupus erythematosus), TM (transverse myelitis), MM (mononeuritis multiplex), PN (peripheral neuropathy), AM (aseptic
meningitis), TPE (therapeutic plasma exchange), INO (intranuclear ophthalmoplegia), CN (cranial neuropathy), ASA (aspirin), N/A (not applicabl

43
Table 3
Cyclophosphamide (CYC)
Population
RCTs
Barile-Fabris et al. N = 32
(2005) SEIZ (11), PN (7), ON (5), TM
(4), Brainstem disease (2),
Coma (2), INO (1)
Stojanovich et al. N = 60
(2003) PSY (8), MD (17), SEIZ (5),
Pilot study CVA (26), ON (37),
Movement disorder (5), AM
(1), DMS (6), COG (7), PN
(19)
Pilot Study
Petri et al. (2010) N = 14 (NPSLE)
Subgroup NPSLE Manifestations not
patients specified
N = 51 (total study
numbers)
Non-controlled trials
Malaviya et al. (1992) N = 14 (NPSLE)
PSY (3), OBS (2), Coma (2),
SEIZ (4), Hemiplegia (1), PN
Response N (%)/
Intervention Comparator
Risk of bias Assessment
IV CYC (19) IVMP (13) IV CYC arm 18/19 (95%)
Dose: 0.75g/m2 BSA SEIZ (5/5), ON (4/4), TM (3/3), PN
monthly (3/4), brainstem disease (1/1), coma
Concurrent Rx: IVMP (32), (1/1), INO (1/1)
prednisone (32) IVMP arm 6/13 (46%)
Risk of bias: high
IV CYC low dose (37) Prednisone (23) IV CYC arm 23/37 (62.2%), relapse
Dose: 0.2-0.4g monthly 14/37 (37.8%)
Concurrent Rx: prednisone Prednisone arm 5/23 (21.7%),
(37) relapse 18/23 (78.3%)
Risk of bias: high
IV CYC high dose (7) IV CYC standard IV CYC standard dose CR 5/7 (71.4%)
Dose: 50mg/kg/d for 4 days dose (7) IV CYC high dose CR 6/7 (86%)
Concurrent Rx: not specified Dose: 0.75g/m2 Crossover patients (from standard to
BSA monthly high dose) CR 2/2 (100%)
Risk of bias: some concerns
IV CYC (14) None Overall response 86%; CR 11/14
Dose: 0.5-0.75g/m2 BSA (79%), PR 1/14 (7%)
every 3wks (6 pulses) 2/14 developed NPSLE while
44
 (1), TM (1)
N = 50 (total study
numbers)
Mok et al. (2003) N = 13
PSY (13)
Galindo-Rodríguez et N = 10
al. (1999) ON (all)
Boumpas et al. (1991) N=9
TM (3), OBS + PSY (2),
Cerebritis + hemiparesis (2),
Cerebritis + SEIZ (1),
Cerebritis + PSY (1)
Observational studies
Fanouriakis et al. N = 46
(2016) PSY (11), PN (6), CVA (5),
SEIZ (5), CN (5), TM (4), MM
(4), AM (3), H/A (2), ACS (2)
Concurrent Rx: PNL (all),
chloroquine/HQL (all)
PO CYC + sequential AZA
(13)
Dose: 1-2mg/kg/d (6m)
Concurrent Rx: IVMP (4),
PNL (13)
IV CYC (10)
Dose: 0.5-1g/m2 monthly for
6m
Concurrent Rx: PO CS (10)
IV CYC (9)
Dose: 0.75g/m2 BSA then
monthly 0.5-1g/m2 BSA
(6m)
Concurrent Rx: IVMP (4),
PNL (9), TPE (1)
IV CYC (44) doses varied
PO CYC (2)
Concurrent Rx: IVMP (43),
AC (1), antiplatelets (4)
receiving IV CYC for other indication
Risk of bias: high
None Overall response 100%; CR 13/13
(100%), relapse 1/13
Risk of bias: high
None Overall response 80%; CR 50%, PR
30%
Risk of bias: high
None Overall response 100%; CR 6/9
(67%), PR 3/9 (33%)
Risk of bias: high
None Overall response 84%; CR 23/50
events (46%), PR 19/50 events (38%)
CYC first line CR 52.4% vs. second line
CR 12.5% (p = 0.018)
Risk of bias: high
45
Wang et al. (2015) N = 17 (cerebral VST)
N = 51 controls (SLE without
cerebral VST)
N = 68 (total study
numbers)
Quintanilla-Gonzalez et N = 19
al. (2017) TM (19: longitudinal
myelitis in 8, NMO in 1)
Controls N = 19 (SLE
patients without NP
manifestations)
Case series
Neuwelt et al. (1995) N = 31
OBS (17), CVA (11), PN (4),
MN (6), H/A (10), SEIZ (9),
PSY (8), TM (5), CN (4), DMS
(5)
Ramos et al. (1996) N = 25
PSY (8), OBS (9), TM (3),
Depression (2), H/A (2), CVA
(1)
Saison et al. (2015) N = 20
IV CYC (17) doses not
specified
Concurrent Rx: IVMP (13), IT
DEX (7), TPE (1), AC (11)
IVMP/IV CYC (15) doses not
specified
IV CYC alone (1)
IVMP alone (3)
Concurrent Rx: TPE (1), AZA
(2), PNL (1)
IV CYC low dose (11)
Dose: 0.25-0.5g/m2 monthly
IV CYC low-mod dose (20)
Dose: 0.5-1g/m2 per
monthly
Concurrent Rx: TPE (8),
warfarin
IV CYC low dose (25)
Dose: 0.5g/wk for 3wks
then 0.5g monthly
Concurrent Rx: CS (25)
IV CYC (11) doses not
None Overall response 13/17 (76.5%), no
relapses
Risk of bias: high
None Overall response at 1yr (only 15 pts
had 1yr F/U) 100%; CR 2/15, PR
13/15, relapse 1/15
Risk of bias: high
None Overall response 19/31 (61%),
stabilisation 9/31 (29%)
Risk of bias: high
None Overall response 96%; CR 17/25
(68%), PR 7/25 (28%), relapse 4/25
(16%) – all responded with re-
treatment
Risk of bias: high
None Overall response 85%; CR 5/20
46
 TM (20) specified (25%), PR 12/20 (60%), relapse 10/17
PO CS (9) responders, multiple relapses 6/17
Concurrent Rx: IVMP (18), (NB: CYC and CS not compared)
PO CS (20), HQL (14), TPE
(3), IVIG (2), AC (6), Risk of bias: high
antiplatelet (2)

Kovacs et al. (2000) N = 14 IVMP/IV CYC (5) various None Overall response 36%; CR 3/14
TM (14) doses (22%); PR 2/14 (14%)
IVMP/IV CYC/TPE (4) Response by treatment:
IVMP (5) IVMP/IV CYC (+/- TPE) 22.2%
Concurrent Rx: PO CS (14), IVMP 60%; CR 2/5, PR 2/5
AC (6)
Risk of bias: high

Martin-Suarez et al. N = 10 (OBS) IV CYC low dose (10) None
(1997) N = 90 (total study Dose: 0.5g/wk until
numbers) response then 0.5g/m vs.
PO CYC vs. AZA
Concurrent Rx: PNL (10)
Overall response 80%; CR 8/10
(80%), 1 relapse – responded with re-
treatment

Barile et al. (1992) N=7 IV CYC (4) 1-1.5g monthly None Response by treatment:
TM (7) IVMP (3) IV CYC 75%; CR 1/4 (25%), PR 2/4
Concurrent Rx: IVMP (4) (50%)
IVMP 100%; CR 1/3 (33%), PR 2/3
(66%)

Risk of bias: high

Tellez-Zenteno et al. N=6 IV CYC (5) doses not None Overall response 4/6 (67%) all PR;

47
(2001) TM (6) specified relapse 3/6 (50%)
IVMP (1) Response by treatment:
Concurrent Rx: IVMP (6), CS IVMP/IV CYC PR 3/5 (60%)
(6), ASA (3), AC (1) IVMP only PR 1/1 (100%)

Risk of bias: high

Hryb et al. (2016) N=5 IV CYC (3) doses not None Overall response 40%
TM (5) specified Response by treatment:
IVMP (2) IV CYC 66.7%; CR 0/3, PR 2/3
Concurrent Rx: IVMP (4), AC IVMP 0%
(3)
Risk of bias: high

Abbreviations: CYC (cyclophosphamide), RCT (randomised controlled trial), N (number), SEIZ (seizure), PN (peripheral neuropathy), ON (optic neuritis), TM (transverse
myelitis), INO (intraocular ophthalmoplegia), IV (intravenous), BSA (body surface area), IVMP (intravenous methylprednisolone), PSY (psychosis), MD (mood disorder), CVA
(cerebrovascular accident), AM (aseptic meningitis), DMS (demyelinating syndrome), COG (cognitive impairment), NPSLE (neuropsychiatric systemic lupus erythematosus),
CR (complete response), PR (partial response), OBS (organic brain syndrome), PNL (prednisolone), HQL (hydroxychloroquine), PO (per oral), AZA (azathioprine), CS
(corticosteroids), TPE (therapeutic plasma exchange), CN (cranial neuropathy), MM (mononeuritis multiplex), H/A (headache), ACS (acute confusional state), AC
(anticoagulation), VST (venous sinus thrombosis), SLE (systemic lupus erythematosus), IT (intrathecal), DEX (dexamethasone), NMO (neuromyelitis optica), NP
(neuropsychiatric), CN (cranial neuropathy), IVIG (intravenous immunoglobulin), ASA (aspirin)

48
Table 4
Synthetic Disease Modifying Agents (studies primarily examining one agent)
Response N (%)/
Population Intervention (N) Comparator (N)
Risk of bias Assessment
MYCOPHENOLATE MOFETIL (MMF)
Post-hoc analysis of
RCT
Ginzler et al. (2010) N = 8 (NPSLE) MMF (3) IV CYC (5) MMF arm CR 3/3 (100%), no relapses
Neurologic manifestations Concurrent Rx: PNL (8) IV CYC arm CR 5/5 (100%), 1 relapse
ALMS trial data not specified; all patients (BILAG), 2 relapses (SELENA-SLEDAI)
had LN
N = 370 (total study Risk of bias: high
numbers)

Observational studies
Gupta et al. (2017) N = 70 (NPSLE excluding MMF (70) None Overall response at 3m: 88.7%; CR
APS) Concurrent Rx (total study 53.22%, PR 35.48%
SEIZ (37), MD (14), COG numbers): IVMP (13), PO Overall response at 12m: 92.37%; CR
(11), ACS (11), AM (2), DMS DEX (8), PO CS (88), HQL 83.9%, PR 8.47%
(6), H/A (4), Movement (88), IVIG +/- RTX (numbers Overall response at final F/U:
Disorder (1), TM (4), ANX not reported) 96.15%; CR 92.31%, PR in 3.84%
(2), PSY (1), Autonomic
neuropathy (1), MN (1), CN Risk of bias: high
(1), PN (1)
N = 88 (total study
numbers)

Tselios et al. (2016) N = 18 (NPSLE) MMF (18) None Overall response 77.8%
OBS (11), H/A (6), PSY (5), Concurrent Rx: IVMP or
‘visual disturbance’ (4), SEIZ increased PO CS Risk of bias: high

49
 (1), CN (1), CVA (1)
N = 177 (total study
numbers)
Salvarani et al. (2015) N = 16
CNS vasculitis (16)
NB: 1 patient excluded due
to short F/U (1 month)
CYCLOSPORIN (CsA)
Case series
Germano et al. (2011) N = 11 (NPSLE)
Neurologic manifestations
not specified
N = 40 (total study
numbers)
INTRA-THECAL METHOTREXATE (MTX)
Observational studies
Wang J et al. (2014) N = 36
PSY (10), ‘conscious
disturbance’ (8), SEIZ (5),
AM (5), CVA (4), Hemiplegia
(4)
N = 36 controls (SLE without
NP manifestations)
MMF (15 with adequate None
F/U)
As initial Rx (8)
As secondary Rx (3)
As maintenance (5)
Concurrent Rx: PO CS (16)
CsA (11) None
Concurrent Rx: CsA/PO
CS/IM MTX (10), IVMP/IV
CYC/IM MTX (30), if
remission: CsA/PO CS/IM
MTX
IT DEX/MTX (36) None
Concurrent Rx: IVMP (36)
Overall response 86.7%
Response by treatment type:
MMF as initial Rx 7/7 (100%)
MMF as secondary Rx 2/3 (66.6%)
MMF as maintenance Rx 4/5 (80%)
Risk of bias: high
Overall response (total study
numbers) 87.5%; ‘excellent’ 23/40
(57.5%); ‘good/fair’ 14/40 (30%),
‘unsatisfactory’ 2/40 (5%) – both
were patients with neurologic
involvement
Risk of bias: high
Overall response 88.9%; remission
28/36 (77.8%), effective 4/36 (11.1%)
Risk of bias: high
50
Case series
Dong et al. (2001) N = 24 IT DEX/MTX (24) None Overall response 91.7%
OBS/coma (6), PSY (5), SEIZ Concurrent Rx: PO CS (24), Response within 48hrs: 17/24 (71%)
(5), AM (3), TM (3), CVA (2) IV CYC, IVIG Response after 2nd IT Rx: 5/24 (21%)

Risk of bias: high

Abbreviations: N (number), MMF (mycophenolate mofetil), RCT (randomised controlled trial), ALMS (Aspreva Lupus Management Study), NPSLE (neuropsychiatric systemic
lupus erythematosus), LN (lupus nephritis), PNL (prednisolone), IV (intravenous), CYC (cyclophosphamide), CR (complete response), BILAG (British Isles Lupus Assessment
Group), SELENA-SLEDAI (Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index), APS (anti-phospholipid syndrome),
SEIZ (seizure), MD (mood disorder), COG (cognitive impairment), ACS (acute confusional state), AM (aseptic meningitis), DMS (demyelinating syndrome), H/A (headache),
TM (transverse myelitis), ANX (anxiety), PSY (psychosis), MN (mononeuropathy), CN (cranial neuropathy), PN (peripheral neuropathy), IVMP (intravenous
methylprednisolone), PO (per oral), DEX (dexamethasone), CS (corticosteroids), HQL (hydroxychloroquine), IVIG (intravenous immunoglobulin), RTX (rituximab), PR (partial
response), F/U (follow up), CVA (cerebrovascular accident), CNS (central nervous system), Rx (treatment), CsA (cyclosporin), IM (intramuscular), MTX (methotrexate), IT
(intrathecal), NP (neuropsychiatric), OBS (organic brain syndrome), hrs (hours)

51
Table 5
Biologic Therapies
Population
RITUXIMAB
Non-controlled trials
Tokunaga et al. (2007) N = 10
ACS (5), PSY (4), SEIZ (2), MD
(2), H/A (1), DMS (1), TM (1),
ANX (1), COG (1)
Tanaka et al. (2007) N = 5 (NPSLE)
ACS (3), MD (2), TM (1),
Depression (1)
N = 15 (total study numbers)
Tokunaga et al. (2005) N=5
Pilot study OBS/SEIZ (2), ‘Sensory
Disorder’ (3), H/A (1)
Observational studies
Iwata et al. (2008) N = 26 (NPSLE)
ACS (6), SEIZ (4), H/A (8), PN
(2), DMS (1), MD (4), TM (2),
PSY (2), COG (4), CVA (6), CN
(1), ANX (2), MM (1)
N = 63 (total study numbers)
Vital et al. (2011) N = 13 (NPSLE)
Manifestations not specified
Intervention
RTX (10)
Refractory patients
Concurrent Rx: PO CS (10),
AZA (1)
RTX (5)
Concurrent Rx: PO CS without
dose escalation allowed
RTX (5)
Refractory patients
Concurrent Rx: CS (10), AZA
(1)
RTX (26)
Refractory patients
Concurrent Rx: CS (all)
*2 patients lost to F/U
RTX (13)
Refractory patients
Response N (%)/
Comparator
Risk of bias Assessment
None Overall response 10/10 100%; CR 6/10
(60%), PR 4/10 (40%), relapse 6/10
(60%)
Risk of bias: high
None Overall response (NPSLE) 5/5 100%;
BILAG A to C: 3/5, BILAC B to C: 2/5
Risk of bias: high
None Overall response 100%; CR 3/5 (60%), PR
2/5 (40%)
Risk of bias: high
None Overall response (NPSLE) 22/24 (91.7%);
BILAG A to C (4), A to D (13), B to D (5)
Imaging response: normal after Rx 2/21,
improved after Rx 10/21
Risk of bias: high
None Overall response (NPSLE) 12/13 (92%);
‘major’ response 12/13 (92%), relapse
52
 N = 39 (total study numbers)
Pinto et al. (2011) N = 12 (NPSLE)
TM (4), PN (4), NMO (1), Not
specified (3)
N = 42 (total study numbers)
Fernandez-Nebro et al. N = 11
(2012) Manifestations not specified
Ramos-Casals et al. N = 6 (NPSLE)
(2010) Manifestations not specified
N = 196 (total study numbers)
Case series
Lu et al. (2009) N = 6 (NPSLE)
OBS (2), CNS vasculitis (1), SEIZ
(2), H/A (1)
N = 50 (total study numbers)
Smith et al. (2006) N = 7 (NPSLE)
Manifestations not specified
N = 22 (total study numbers)
Concurrent Rx: IVMP (13), PNL
(13), IV CYC (3)
RTX (12)
Refractory patients
Concurrent Rx: IVMP (12), pre-
meds (12), PNL (12)
RTX (11)
Refractory patients
Concurrent Rx: IVMP, pre-
medication
RTX (6)
Refractory patients
Concurrent Rx: CS (6), unclear
if/which NPSLE cases received
CYC or MMF
RTX (6)
Refractory patients
Concurrent Rx: IVMP (6), IV
CYC (6)
RTX (7)
Refractory patients
Concurrent Rx: IV CYC 500mg
w first RTX infusion (7), PO CS
(7), MMF (4), AZA (2)
1/12 (8%) responders
Risk of bias: high
None Overall response (NPSLE) 75%, relapse
2/9 (22%) responders. Both re-treated
and with response
Risk of bias: high
None Overall response 73%
Risk of bias: high
None Overall response (NPSLE) 80%; CR 5/6
(80%)
Risk of bias: high
None Overall response (NPSLE) 83.33%; CR 4/6
(66.7%), PR 1/6 (16.7%)
Risk of bias: high
None Overall response (NPSLE) 100%; CR 4/7
(57%), PR 3/7 (43%), relapse 4/7 (57%)
responders. 2/4 re-treated and had CR
Risk of bias: high
53
Ye et al. (2011) N=6 RTX (6) None Overall response 83%; CR 4/6 (66.7%),
TM (6) Concurrent Rx: IVMP (6), HQL PR 1/6 (16.7%), relapse 2/5 (40%) of
responders. 1 re-treated and had CR

Risk of bias: high

Hickman et al. 2015 N=5
Manifestations not specified
BELIMUMAB
Post-hoc analysis of RCT
Manzi et al. (2012) N = 45 (NPSLE)
N = 21 (NPSLE cases with data
BLISS-52 presented)
BLISS-76 H/A (24/45 but unclear how
many had outcome data),
other neurologic
manifestations not specified
N = 1684 (total study
numbers)
RTX (5)
Refractory patients
Concurrent Rx: IVMP (5), PNL
(5), IV CYC (3)
BEL (15)
1mg/kg (8)
10mg/kg (7)
Concurrent Rx (pooled data
from both studies): HQL, CS,
AZA, MTX, MMF, CsA, LFN
None Overall response 100%; CR 2/5 (40%), PR
3/5 (60%), relapses 4/5 (80%). All re-
treated and had either PR or CR
Risk of bias: high
Placebo + Overall response (NPSLE):
standard of care BILAG improvement: BEL 1mg/kg 75%,
(6) BEL 10mg/kg 42.9%, placebo 83.3%
SELENA-SLEDAI improvement: BEL
1mg/kg 60%, BEL 10mg/kg 63.2%,
placebo 9.1%
NPSLE + high serologic activity: BEL
1mg/kg 66.7%, BEL 10mg/kg 66.7%,
placebo 0%
H/A subgroup (note N missing data
unknown): BEL 1mg/kg 100%, BEL
10mg/kg 69.2%, placebo 20%

Risk of bias: high

Observational studies
Hui-Yuen et al. (2015) N = 9 (NPSLE) BEL (9) None Overall response (NPSLE) 0%
Manifestations not specified Concurrent Rx: antimalarials, Development or worsening of NPSLE
N = 195 (total study numbers) CS, AZA, MMF while receiving belimumab 6/158

Risk of bias: high

54
Abbreviations: N (number), ACS (acute confusional state), PSY (psychosis), SEIZ (seizure), MD (mood disorder), H/A (headache), DMS (demyelinating syndrome), TM
(transverse myelitis), ANX (anxiety), COG (cognitive impairment), RTX (rituximab), PO (per oral), CS (corticosteroids), AZA (azathioprine), Rx (treatment), CR (complete
response), PR (partial response), NPSLE (neuropsychiatric systemic lupus erythematosus), BILAG (British Isles Lupus Assessment Group), OBS (organic brain syndrome), PN
(peripheral neuropathy), CVA (cerebrovascular accident), CN (cranial neuropathy), MM (mononeuritis multiplex), F/U (follow up), NMO (neuromyelitis optica), PNL
(prednisolone), IVMP (intravenous methylprednisolone), CYC (cyclophosphamide), MMF (mycophenolate mofetil), CNS (central nervous system), IV (intravenous), RCT
(randomised controlled trial), BLISS (A Study of Belimumab in Subjects with Systemic Lupus Erythematosus), BEL (belimumab), HQL (hydroxychloroquine), MTX
(methotrexate), CsA (cyclosporin), LFN (leflunomide), SELENA-SLEDAI (Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity
Index)

55
Table 6
Therapeutic plasma exchange (TPE)
Population
THERAPEUTIC PLASMA EXCHANGE (TPE)
Non-controlled trials
Bambauer et al. (2000) N = 18
Neurologic manifestations
mentioned: PSY, OBS
(numbers not specified)
Observational studies
Neuwelt et al. (2003) N = 26
ACS (13), SEIZ (10), CVA (7),
COG (5), DMS (4), H/A (4),
TM (4), PSY (5), AM (2), MD
(3), Chorea (2), ANX (1)
Case series
Bartolucci et al. (2007) N = 10 (13 events)
COG (8), AM (6), PSY (6),
SEIZ (4), TM (4), CVA (4),
ACS (3), MD (3), H/A (2),
DMS (1)
Aguirre-Valencia et al. N = 9 (NPSLE)
(2019) Manifestations: not
specified
Intervention
TPE (18)
Concurrent Rx: CS (18), CsA
(18), IV CYC (18)
TPE (26)
Concurrent Rx: PO CS (23),
IV CYC (16), AZA (2), IVIG
(1), Chlorambucil (2), AC (2)
TPE (10)
Concurrent Rx: IVMP (10),
PNL (10), IV CYC (9), AC (4),
IVIG (1)
TPE (9)
Concurrent Rx: unclear
which patients received
Comparator Response N (%)/
Risk of bias Assessment
None Overall response 100%;
documentation of response:
“neuropsychiatric disorders
disappeared completely”
Risk of bias: high
None Overall response 20/26 (74%)
Risk of bias: high
None Overall response 100%; CR 7/13
events (54%); PR 6/13 events (46%)
Note: CRs had a shorter time to TPE
following 1st CYC pulse: ave. 0.6wks
vs. 3.6wks in PRs
Risk of bias: high
None Overall response 77.8%
Risk of bias: high
56
 N = 66 (total study other Rx
numbers)

Soyuöz et al. (2017) N = 5 (NPSLE) TPE (5) None Overall response 80%; CR 3/5 (60%),
PSY (1), NMO (1), MG (2), Concurrent Rx: PO CS (all), PR 1/5 (20%)
TM (1) IVMP/CYC (2),
N = 23 (total study IVMP/CYC/RTX + repeat TPE Risk of bias: high
numbers) (1)

Hashimoto et al. (1998) N = 5 (NPSLE) TPE (5) None Overall response 5/5 (100%)
‘conscious disturbance’ (2), Concurrent Rx: PNL (dose
‘CNS lupus’ (1), ‘emotional 10-100mg/d) Risk of bias: high
lability’ (1), CVA (1)
N = 30 (total study
numbers)

Abbreviations: TPE (therapeutic plasma exchange), N (number), PSY (psychosis), OBS (organic brain syndrome), Rx (treatment), CS (corticosteroids), CsA (cyclosporin), IV
(intravenous), CYC (cyclophosphamide), ACS (acute confusional state), SEIZ (seizures), CVA (cerebrovascular accident), COG (cognitive impairment), DMS (demyelinating
syndrome), H/A (headache), TM (transverse myelitis), AM (aseptic meningitis), MD (mood disorder), ANX (anxiety), PO (per oral), AZA (azathioprine), IVIG (intravenous
immunoglobulin), AC (anticoagulation), PNL (prednisolone), CR (complete response), PR (partial response), NMO (neuromyelitis optica), MG (myasthenia gravis), RTX
(rituximab), IVMP (intravenous methylprednisolone), CNS (central nervous system)

57
Table 7
Intravenous immunoglobulin (IVIG)
Population Comparator Response N (%)/
Intervention
Risk of bias Assessment
INTRAVENOUS IMMUNOGLOBULIN (IVIG)
Case series
Camara et al. (2014) N = 11 (NPSLE) IVIG (11) None Overall response 8/11 (73%); CR 4/11
PN (5), PSY (2), CNS Concurrent Rx: not specified (36%), PR 4/11 (36%)
vasculitis (1), ACS (3)
N = 52 (total study Risk of bias: high
numbers)

Vina et al. (2005) N=6 IVIG (6) None Overall response 3/6 (50%)
CIDP (6) Concurrent Rx: IVMP (1), PO
CS (4), TPE (3) Risk of bias: high

Abbreviations: IVIG (intravenous immunoglobulin), N (number), NPSLE (neuropsychiatric systemic lupus erythematosus), PN (peripheral neuropathy), PSY (psychosis), CNS
(central nervous system), ACS (acute confusional state), Rx (treatment), CR (complete response), PR (partial response), CIDP (chronic inflammatory demyelinating
polyneuropathy), IVMP (intravenous methylprednisolone), PO (per oral), CS (corticosteroids), TPE (therapeutic plasma exchange)

58
Table 8
Autologous Stem Cell Transplant (auto-SCT)
Population
AUTOLOGOUS STEM CELL TRANSPLANT (Auto-SCT)
Non-controlled trials
Burt et al. (2006) N = 18 (NPSLE)
TM, ‘Cerebritis’ (manifested
as: SEIZ, PSY, paraparesis,
H/A, AM or CVA)
N = 50 (total study
numbers)
Observational studies
Jayne et al. (2004) N = 24 (CNS-SLE)
N = 5 (PNS-SLE)
NB: Total N of NPSLE
patients in study is unclear,
as patients with CNS and
PNS NPSLE may overlap
Manifestations: not
specified
N = 58 (total study
numbers)
Alchi et al. (2013) N = 12 (NPSLE)
Manifestations: not
specified
Comparator
Intervention
Auto-SCT (18) None
Mobilisation: IV CYC + G-CSF
Conditioning: IV CYC + ATG
Concurrent Rx: AC (if
previous APS diagnosis)
Auto-SCT (unclear) None
Mobilisation: IV CYC + G-CSF
vs. IV CYC vs. G-CSF alone
Conditioning: IV CYC + ATG
vs. combinations of IV CYC,
busulphan, etoposide,
fludarabine, melphalan,
thiotepa, BEAM
Auto-SCT (12) None
Mobilisation: IV CYC + G-CSF
vs. G-CSF alone
Response N (%)/
Risk of bias Assessment
Overall response (total study
numbers):
Probability of 5yr survival 84%
Probability of disease remission at
5yrs 50%
NPSLE patients not reported
separately
Risk of bias: high
Change in frequency of CNS Sx:
46% at baseline to approx. 5% at 6m,
then approx. 10% at 12m
One patient developed new CNS
disease post auto-SCT
Risk of bias: high
Overall survival (total study
numbers):
5-yr overall survival 81±8%
59
 N = 28 (total study Conditioning: IV CYC or 5-yr disease-free survival 29±9%
numbers) melphalan alone vs. IV CYC Relapse incidence at 5yrs 56±11%
+ various combinations of NPSLE patients not reported
ATG, IVMP, fludarabine, separately
thiotepa, alemtuzumab,
melphalan Risk of bias: high

Abbreviations: auto-SCT (autologous stem cell transplant), N (number), NPSLE (neuropsychiatric systemic lupus erythematosus), TM (transverse myelitis), SEIZ (seizure), PSY
(psychosis), H/A (headache), AM (aseptic meningitis), CVA (cerebrovascular accident), IV (intravenous), CYC (cyclophosphamide), G-CSF (granulocyte colony stimulating
factor), ATG (anti-thymocyte globulin), Rx (treatment), AC (anticoagulation), APS (antiphospholipid syndrome), yr (year), CNS (central nervous system), PNS (peripheral
nervous system), SLE (systemic lupus erythematosus), BEAM (conditioning protocol consisting of: carmustine, etoposide, cytarabine, melphalan)

60
Table 9
Other Therapies
Response N (%)/
Population Intervention Comparator
Risk of bias Assessment
Case reports/small series
Bica et al. (2015) N=3 ECT (3) None Response 3/3 (100%)
PSY/Catatonia (3) Recent (failed) Rx: IVMP (3),
IV CYC (3), RTX (1), IVIG (1) Risk of bias: high

Tan et al. (2013) N=3 ECT (3) None Response 3/3 (100%)
PSY/MD (3) Concurrent Rx: IVMP (2), IV
HC (3), IV CYC (3), PNL (3) Risk of bias: high

Mok et al. (2008) N=1 Immunoablative IV CYC None PR

NMO Recent Rx (3m prior): IVMP,
IVIG, TAC, PO CYC, RTX Risk of bias: high

Graninger et al. (2002) N = 1 (SEIZ) Immunoadsorption (IA) None CR

N = 5 (total study numbers) Concurrent Rx: IV CYC, high
dose PNL Risk of bias: high

Kizu et al. (2011) N=1 Tacrolimus (TAC) None CR

CVA (CNS vasculitis) Concurrent Rx: IVMP, PNL
Risk of bias: high

Pfausler et al. (1995) N=1 CSF Pheresis None CR

PSY + CVA (presumed CNS Concurrent Rx: IVMP, IV
vasculitis) CYC, high dose PNL Risk of bias: high

Stahl et al. (2000) N=1 CSF Pheresis None CR

61
 DMS Concurrent Rx: IVMP, IV
CYC, IA Risk of bias: high

Mathieu et al. (2002) N=1 Iloprost None CR

COG Concurrent Rx: nil

Abbreviations: N (number), PSY (psychosis), ECT (electroconvulsive therapy), Rx (treatment) IVMP (intravenous methylprednisolone), IV (intravenous), CYC
(cyclophosphamide), RTX (rituximab), IVIG (intravenous immunoglobulin), MD (mood disorder), HC (hydrocortisone), PNL (prednisolone), NMO (neuromyelitis optica), TAC
(tacrolimus), PO (per oral), PR (partial response), SEIZ (seizure), IA (immunoadsorption), CR (complete response), CVA (cerebrovascular accident), CNS (central nervous
system), CSF (cerebrospinal fluid), DMS (demyelinating syndrome), COG (cognitive impairment)

62
Table 10
Combination Therapies
Population
Observational studies
Bortoluzzi et al. (2012) N = 31 (severe NPSLE), 35
events
PSY (8 events), ACS (3), PN
(5 events), ON (2), AM (2),
Chorea (2 events), COG (3),
DMS (2), CVA (3), H/A (3),
SEIZ (1), MG (1)
N = 231 (total study
numbers)
Lu et al. (2008) N = 14
TM (14)
Controls N = 23
Comparator Response N (%)/
Combinations used
Risk of bias Assessment
IV CS/IV CYC/IVIG/TPE (1) None Overall response 74%
IV CS/IV CYC/TPE (1) SLEDAI decrease by mean of 6
IV CS/CYC/IVIG (1) (p<0.001)
IV CS/TPE then AZA (1) ECLAM decrease by mean of 2.6
IV CS/IVIG then CYC (1) (p<0.001)
IV CS/IVIG then MMF (1) Response by therapy used:
AZA/TPE then RTX (1) MMF used in 1 case: ‘fairly effective’
IV CS/IV CYC (2) IVIG used in 4 cases: ‘good results,
IV CS/PO CYC (2) especially on peripheral neuropathy’
IV CS/RTX (1) RTX used in 2 cases: ‘significant
PO CYC/TPE (3) improvement’
One agent: IV CS (9), CYC TPE used in 7 cases: ‘combined with
(5), AZA (3), CsA (1), MMF immunosuppressive therapy
(1) provided rapid and intensive
Concurrent Rx: AC (19), therapeutic effect’
anti-platelet (4)
Risk of bias: high
IVMP/IV CYC/IT DEX (3) None Overall response 50% ‘good
IVMP/IV CYC/RTX (1) outcome’
IVMP/IVIG/AZA (1) Response by therapy used:
IVMP/IV CYC (1) IVMP/IV CYC/IT DEX 1/3
PO CS/IV CYC (3) IVMP/IV CYC/RTX 0/1
PO CS/IT DEX (1) IVMP/IVIG/AZA 1/1
One agent: IVMP (2), PO CS IVMP/IV CYC 1/1
63
 (2) PO CS/IV CYC 1/3
PO CS/IT DEX 0/1
IVMP alone 2/2, PO CS alone ½

Risk of bias: high

Case series
D’Cruz et al. (2004) N = 12 IVMP/IV CYC/AZA (2) None Overall response 100%; CR 3/12, PR
TM (12) IVMP/IV CYC/MTX (1) 9/12, relapse: at least 1/12
PNL/IV CYC/AZA (3)
IVMP/IV CYC (2) Risk of bias: high
PNL/IV CYC (1)
PNL/AZA (1)
One agent: IVMP (1), PNL
(1)
Concurrent Rx: AC (6), ASA
(3)

Pego-Reigosa et al. N = 10 IVMP/IV CYC/TPE (1) None Overall response 100%; CR 6/10
(2008) PSY (10) IVMP/AZA/TPE (1) (60%), PR 4/10 (40%), relapse (CRs):
IVMP/IV CYC (3) 3/6 (50%)
IVMP/TPE (1) Response by Rx used:
High dose PNL/AZA (1) IVMP/IV CYC/TPE PR 1/1
Mod dose PNL/AZA (2) IVMP/AZA/TPE CR 1/1
Mod dose PNL only (1) IVMP/IV CYC CR 3/3 (relapse 1/3)
IVMP/TPE CR 1/1 (relapsed)
High dose PNL/AZA CR 1/1 (relapsed)
Mod dose PNL/AZA PR 2/2 (chronic)
Mod dose PNL only PR 1/1

Risk of bias: high

64
Kampylafka et al. N=9 IV CS/IV CYC/IVIG/RTX (2) None Overall response 100%
(2016) SEIZ (all) IV CS/IV CYC/IVIG/TPE (1) “SLE-epilepsy patients in our study
IV CS/IV CYC/IVIG (2) showed a satisfactory therapeutic
IV CS/IV CYC (3) response”
PO CS alone (1)
Risk of bias: high

Chessa et al. (2017)
N=5 IVMP/IV CYC/RTX then None Overall response 100%; CR 3/5, PR
DMS (all) MMF (1) 2/5, relapse 1/5
IVMP/IV CYC then AZA (1) Response by therapy used:
IVMP/PO CYC (1) IVMP/IV CYC/RTX then MMF: CR
IV CYC then MMF (1) IVMP/IV CYC then AZA: PR
IVMP alone (1) IVMP/PO CYC: PR (clinical), CR
(imaging)
IV CYC then MMF: CR
IVMP: CR

Risk of bias: high

Abbreviations: N (number), NPSLE (neuropsychiatric systemic lupus erythematosus), PSY (psychosis), ACS (acute confusional state), PN (peripheral neuropathy), ON (optic
neuritis), AM (aseptic meningitis), COG (cognitive impairment), DMS (demyelinating syndrome), CVA (cerebrovascular accident), H/A (headache), SEIZ (seizure), MG
(myasthenia gravis), IV (intravenous), CS (corticosteroid), CYC (cyclophosphamide), IVIG (intravenous immunoglobulin), TPE (therapeutic plasma exchange), AZA
(azathioprine), MMF (mycophenolate mofetil), RTX (rituximab), PO (per oral), CsA (cyclosporin), AC (anticoagulation), SLEDAI (Systemic Lupus Erythematosus Disease
Activity Index), ECLAM (European Consensus Lupus Activity Measurement), TM (transverse myelitis), IVMP (intravenous methylprednisolone), IT (intrathecal), DEX
(dexamethasone), MTX (methotrexate), PNL (prednisolone), CR (complete response), PR (partial response), Rx (treatment)

65
Table 11
Various Therapies Received
Population
Observational studies
Joseph et al. (2007) N = 41
H/A (22), SEIZ (17), ‘visual
failure’ (13), hemiparesis
(10), COG (10), confusion
(10), ‘personality change’
(8), depression (7), CVA (7),
MD (4), TM (2), AM (2)
Fargetti et al. (2019) N = 38
PN (38)
Mok et al. (1998) N = 10
Therapies used
CS (36), AZA (10), CYC (9),
IVIG (2), TPE (2), MMF (1),
CsA (1)
Concurrent Rx:
HQL (12), antiplatelets, AC
(6), anti-epiletpics, anti-
parkinsonian Rx
CYC (19), AZA (16), MMF None
(2), IVIG (1), CS alone (1)
Concurrent Rx:
PO CS (76.3%), IV CS (55.2%)
PO CYC (4), IV CYC (2), AZA
Comparator Response N (%)/
Risk of bias Assessment
None Overall response (including minor
and moderate resulting disability)
86%; CR 12%, PR 74%, relapse 78%
CYC (9): overall response 4/9 (44.4%)
Minor disability (4), severe disability
(4), NR/death (1)
AZA (10): overall response 9/10
(90%)
Asymptomatic (2), minor disability
(5), moderate disability (2), NR/death
(1)
TPE (2): overall response 1/2 (50%)
Moderate disability (1), NR/death (1)
Risk of bias: high
Overall response at 12m 92%, 5yr
89%
At 12m: CR 36.8%, PR 55.2%
At 5yrs: CR 35.7%, PR 53.6%, flare
3/38 (10.7%)
Risk of bias: high
None Overall response: 80%
66
 TM (10) (3), PO CS only (1)
Controls N = 143 Concurrent Rx: IVMP (8), PO
CS (2), TPE (1), AC (2)
Case series
Ahn et al. (2019) N = 16 IVMP (15), IV CYC (8), TPE
TM (16, NMO in 1) (2), RTX (1)
Combinations used:
IVMP/IV CYC/TPE (2),
IVMP/IV CYC (6), IVMP/RTX
(1), IVMP alone (6), PO CS
(1)
Concurrent Rx:
PO CS (16)
Riviere et al. (2017) N = 10 IV CYC (6), RTX (3), MMF (1)
MM (10) Concurrent Rx: IVMP (6), PO
CS (10), IVIG (1)
‘8/10 patients improved within 7
days Rx with high dose CS’
Response by Rx used:
IV CYC CR 1/1
PO CYC CR 2/4, PR 2/4
PO CYC to IV CYC/TPE NR 1/1
AZA: PR 3/3
PO CS only: CR 1/1, relapse
Risk of bias: high
None Overall FR (favourable response)
75%; CR 10/16 (62.5%), PR 2/15
(12.5%)
Response by Rx:
IVMP/IV CYC/TPE: FR 2/2
IVMP/IV CYC: FR 5/6, 2 relapses
IVMP/RTX: FR 0/1
IVMP alone: FR 5/6, 3 relapses
PO CS: FR 0/1, death
Risk of bias: high
None Overall response (includes
stabilisation) 100%; CR 0/10, PR 7/10,
stabilisation 3/10, relapse 2/10
Response by Rx:
IV CYC: PR 4/6, stabilisation 2/6
RTX: PR 2/3, stabilisation 1/3
MMF: PR 1/1
67
 Risk of bias: high

Abbreviations: N (number), H/A (headache), SEIZ (seizure), COG (cognitive impairment), CVA (cerebrovascular accident), MD (mood disorder), TM (transverse myelitis), AM
(aseptic meningitis), CS (corticosteroids), AZA (azathioprine), CYC (cyclophosphamide), IVIG (intravenous immunoglobulin), TPE (therapeutic plasma exchange), MMF
(mycophenolate mofetil), CsA (cyclosporin), Rx (treatment), HQL (hydroxychloroquine), AC (anticoagulation), CR (complete response), PR (partial response), NR (no
response), PN (peripheral neuropathy), PO (per oral), IV (intravenous), NMO (neuromyelitis optica), IVMP (intravenous methylprednisolone), RTX (rituximab), FR
(favourable response), MM (mononeuritis multiplex)

68
Table 12
Observational studies with Therapy-specific Associations
Population
Zirkzee et al. (2014) N = 169
CVA (77), COG (65), H/A
(46), SEIZ (40), PSY (22),
MD (21), Myelopathy
(10), ACS (10), PN (9), CN
(7), Aseptic meningitis (4),
Plexopathy (2)
Andrade et al. (2008) N = 40 (NPSLE)
SEIZ (all)
N = 600 (total study
numbers)
Hanly et al. (2012) N = 78 (NPSLE events)
SEIZ (all)
N = 1631 (total study
numbers)
Association Identified Findings
Antiplatelet therapy was Multivariate analysis:
associated with a Antiplatelet therapy was a/w reduction in mortality (HR 0.22
reduction in mortality (95% CI 0.07–0.74))
For patients with CVA: HR 0.17 (95% CI 0.04–0.75)
For patients without CVA: HR 0.48 (95% CI 0.06–3.60).
No associations were found for other therapies (CYC, AZA,
IVMP, PO CS, oral anticoagulation)
HQL use was associated Univariable analysis:
with a longer time to Ave. dose of glucocorticoids (HR=1.03; 95% CI 1.01 to 1.05;
seizure occurrence p<0.0001) and cyclophosphamide use (HR=2.54; 95% CI 1.36
to 4.74; p=0.0034) a/w shorter time to seizure occurrence
Use of HQL (HR=0.18; 95% CI 0.01 to 0.34; p<0.0001) a/w
longer time to seizure occurrence
Multivariable analysis:
Use of HQL (HR=0.35; 95% CI 0.15 to 0.80; p=0.0131) a/w
longer time to seizure occurrence
Prior use of antimalarial Single factor analysis:
medication in the Use of CS a/w increased risk of seizure occurrence
absence of Use use of antimalarial medications a/w reduced risk of
immunosuppressive seizure occurrence
agents was associated Multivariate analysis:
with a reduced risk of Corticosteroids a/w increased risk of seizures (but with a wide
seizures CI)
Prior use of antimalarial medications in the absence of
immunosuppressive agents a/w reduced risk of seizures (HR
69
 0.7 (0.01 – 0.66))

Feng et al. (2011) N = 122 (NPSLE) Antimalarial medications Logistic regression analysis:
SEIZ (all) were associated with low Antimalarial drugs were independently associated with low
N = 1956 (total study incidences of neurological incidences of neurological involvement [OR 0.61 (0.40, 0.92),
numbers) involvement p = 0.02] but not the SLEDAI score at admission [OR 1.10
(0.84, 1.43), p = 0.49]

González et al. N = 185 (with NP damage) Both the use of HQL and Univariable analysis:
(2009) COG (130), CVA (45), SEIZ the use of moderate dose Weighted ave. max. prednisone dose and prednisone dose
(30), CN/PN (22), PSY (5), prednisone (10-30mg/d) >30mg/d a/w a shorter time to NP damage
TM (3) were associated with a Mod. dose prednisone (10-30mg/d) and HQL use a/w a longer
N = 632 (total study longer time to NP damage time to NP damage
numbers) Multivariable analysis:
Mod. dose prednisone (HR = 0.56; 95% CI, 0.35–0.92) and HQL
use (HR = 0.58; 95% CI 0.36–0.93) a/w a longer time to NP
damage

Mok et al. (2001) N = 96 (NPSLE), 133 Previous HQL use was Univariate analysis:
events negatively associated Previous CYC (OR 4.5, p < 0.001) and AZA (OR 2.6, p < 0.001)
SEIZ (28%), CVA (19%), with the development of use were positively a/w the development of NPSLE
ACS (14%), PSY (11%), TM NPSLE, while previous Previous HQL use (OR 0.4, p = 0.001) was negatively a/w the
(8%), MD (6%), H/A (4%), CYC use was positively development of NPSLE
CN (3%), Movement a/w the development of Multivariate analysis:
disorder (2%), DMS NPSLE Previous CYC use (RR 4.3, p <0.001) was positively a/w the
(1.5%), ANX (1.5%), MN development of NPSLE
(1.5%), AM (1%), PN (1%) Previous HQL use (RR 0.5, p = 0.02) was negatively a/w the
N = 518 (total study development of NPSLE
numbers)

70
Mok et al. (2006) N = 65 (NPSLE), 115
events
CVA (31), SEIZ (25), PSY
(23), ACS (15), MD (18),
COG (13), CN (12), H/A
(11), myelopathy (8),
movement disorder (2),
MN (2), AM (1)
N = 280 (total study
numbers)
IVMP was an independent Univariate analysis:
predictor of NP damage Pulse methylprednisolone a/w NP damage
HQL use protective against NP damage
Multiple regression model:
Pulse methylprednisolone was an independent predictor of
NP damage

Abbreviations: N (number), CVA (cerebrovascular accident), COG (cognitive impairment), H/A (headache), SEIZ (seizure), PSY (psychosis), MD (mood disorder), ACS (acute
confusional state), PN (peripheral neuropathy), CN (cranial neuropathy), HR (hazard ratio), CI (confidence interval), CYC (cyclophosphamide), AZA (azathioprine), IVMP
(intravenous methylprednisolone), PO (per oral), CS (corticosteroids), NPSLE (neuropsychiatric systemic lupus erythematosus), HQL (hydroxychloroquine), SLEDAI (), OR
(odds ratio), TM (transverse myelitis), NP (neuropsychiatric), DMS (demyelinating syndrome), ANX (anxiety), MN (mononeuropathy), AM (aseptic meningitis)

71
Table 13: Summary of Studies Included in the Systematic Review

Treatment Used Number of Studies, Number of Patient Risk of Bias Recommendation/Strength

Corticosteroids
Cyclophosphamide
Synthetic DMARDs (studies
primarily examining one agent)
(mycophenolate, intrathecal
patients (NPSLE manifestations
only)
14 studies, N = 199 patients
Non-controlled trials: 2
Observational studies: 2
Case series: 10
18 studies, 352 patients
RCTs: 2
Pilot study: 1
Non-controlled trials: 4
Observational studies: 3
Case series: 8
7 studies, 183 patients
Post-hoc analysis of RCT: 1
Observational studies: 4
population of recommendation
(manifestations)
Mixed patient High in all Low-moderate evidence
population: 6 supports benefit, based on
Myelitis: 4 consistent data in a large
Optic neuritis: 2 number of observational
Cranial studies and case series.
neuropathy: 1
Chorea: 1 Subgroup data: limited
evidence supports benefit
in myelitis and optic
neuritis, albeit with high
rates of relapse; case series
data only
Mixed patient High in 17/18 Moderate evidence
population: 7 Some concerns supports benefit, based on
Myelitis: 6 in 1/18 consistent data in a large
Psychosis: 1 number of studies and
Optic neuritis: 1 some RCT data.
Organic brain
syndrome: 1 Subgroup data: limited
Cerebral VST: 1 evidence for use in myelitis;
Not specified: 1 case series data only
Mixed patient High in all Mycophenolate: limited
population: 4 evidence supports benefit
CNS vasculitis: 1 Intrathecal methotrexate:

72
methotrexate, cyclosporin)
Biologic Therapies
(rituximab, belimumab)
Therapeutic Plasma Exchange
Intravenous Immunoglobulin
Autologous Stem Cell
Case series: 2
14 studies, 166 patients
Post-hoc analysis of RCTs: 1
Non-controlled trials: 3
Observational studies: 6
Case series: 4
6 studies, 73 patients
Non-controlled trials: 1
Observational studies: 1
Case series: 4
2 studies, 17 patients
Case series: 2
3 studies, 59 patients
Not specified: 2 limited data suggests
benefit, confounded by
concomitant therapies
Cyclosporin: conflicting
data
Subgroup data: limited
evidence; single case series
data only
Mixed patient High in all Rituximab: low-moderate
population: 7 evidence for benefit,
Myelitis: 1 especially in refractory
Not specified: 6 disease; based on
consistent data in
numerous (12) studies
Belimumab: conflicting
data
Mixed patient High in all Limited evidence supports
population: 5 benefit as adjunctive
Not specified: 1 treatment
Subgroup data: nil
Mixed patient High in all Limited evidence for
population: 1 benefit as adjunctive
CIDP: 1 treatment
Subgroup data: limited
evidence; single case series
data only
Mixed patient High in all Limited evidence for
73
Transplant Non-controlled trials: 1 population: 1 benefit in refractory
Observational studies: 2 Not specified: 2 disease

Subgroup data: nil

Other Therapies 8 studies, 12 patients Mixed patient High in all Weak evidence; case report
(ECT, immunoablative IV CYC, Case series: 2 population: 1 data or small series only
immunosdsorption, tacrolimus, Case reports: 6 PSY/MD: 2
CSF pheresis, iloprost) NMO: 1 Subgroup data: weak
SEIZ: 1 evidence, as above
CVA: 1
DMS: 1
COG: 1
Combination Therapies 6 studies, 81 patients Mixed patient High in all Limited data supports
Observational studies: 2 population: 1 improved response with
Case series: 4 Myelitis: 2 combination therapy
PSY: 1
SEIZ: 1 Subgroup data: limited
DMS: 1 evidence; case series data
only
Various therapies used, only 5 studies, 115 patients Mixed patient High in all Limited evidence supports
some results reported Observational studies: 3 population: 1 benefit of azathioprine in
Case series: 2 Myelitis: 2 NPSLE treatment
PN: 1
MM: 1 Subgroup data: limited data
supports IVMP and IV CYC
in myelitis
Observational Studies with 7 studies, 455 patients Mixed patient High in all Hydroxychloroquine:
Therapy-specific Associations population: 4 limited evidence supports
SEIZ: 3 reduction in time to
development of NPSLE and

74
damage, based on
observational data
Antiplatelet therapy:
limited evidence supports
reduction in mortality (in
absence of CVA), single
observational study

Subgroup data: limited

evidence supports use of
hydroxychloroquine in
patients with seizures

75
 7222 studies identified in search

2312 duplicates removed

4813 studies excluded:

4910 studies screened (title and abstract)
NPSLE manifestations not included in study
Treatment not included in study
Treatment used for other conditions: non-
neuropsychiatric lupus, inflammatory bowel
disease
Insufficient outcome data reported
Reviews, comment, basic science papers
Paediatric papers

29 studies excluded:
97 studies thoroughly reviewed Case reports, case series N<5, abstracts
Outcomes not sufficiently reported
APS without other NPSLE
1 study used same data set as another study

22 studies identified through hand-search

90 studies included in analysis

Fig. 1. Process of study selection.

76
  Hydroxychloroquine: low level evidence from observational data for benefit
ALL  *Symptomatic therapy as required (anticonvulsants, antidepressants, anxiolytics,
NPSLE antipsychotics), at the discretion of the treating physician

DISEASE  Early initiation of corticosteroids (PO or IV): accepted first-line therapy despite no
SEVERITY clinical trial data. Can be used as monotherapy or in combination with synthetic DMARD
 Consider synthetic DMARD
MILD o Azathioprine: limited evidence supports benefit for both acute and maintenance
management
o Mycophenolate: limited evidence supports benefit

 Early initiation of corticosteroids (PO or IV) PLUS synthetic DMARD:

MOD o Azathioprine: as above
o Mycophenolate: as above

 Early initiation of IV corticosteroids PLUS:

o IV cyclophosphamide: moderate evidence supports benefit, based on consistent
data in numerous studies and minimal trial data.
SEVERE
OR if cyclophosphamide contraindicated, consider
o Rituximab: low-moderate evidence favours benefit, based on consistent data in
numerous studies. No clinical trial data.
 Consider adjuvant therapy:
o IVIG: limited evidence supports benefit as adjuvant therapy
o TPE: limited evidence supports benefit as adjuvant therapy

 Rituximab: as above
REFRACTORY  Consider autologous SCT: limited data favour benefit in refractory disease

COEXISTING
 *Add anticoagulation for patients with associated antiphospholipid syndrome
APS

Fig. 2. Suggested Treatment Algorithm for the Management of Inflammatory NPSLE

Abbreviations: NPSLE: neurologic and psychiatric manifestations of systemic lupus erythematosus, mod: moderate, APS:
antiphospholipid syndrome, PO: per oral, IV: intravenous, DMARD: disease modifying antirheumatic drug, IVIG: intravenous
immunoglobulin, TPE: therapeutic plasma exchange, SCT: stem cell transplant
*Data not reviewed in this systematic review

Note: there is no requirement for this figure to be published in colour

77