Neuropsychiatric lupus: a mosaic of clinical presentations

Epidemiology

The prevalence of SLE varies among populations and is approximately 50 in 100,000
3]. However, the estimate of NPSLE is challenging owing to variations in study designs
(prospective or retrospective), follow-up periods, the uniformity of case definitions,
and disease age population evaluated (pediatric vs. adult). To overcome this obstacle,
the 1999 ACR-NPSLE case definitions have been widely used; however, despite this,
estimates of the prevalence of NPSLE has still ranged considerably 4]. Unterman et al.5] performed a meta-analysis of studies assessing NPSLE prevalence. According to 10
high-quality prospective studies, which included 2,049 SLE patients, the prevalence
of NPSLE manifestations among them was 56%. Among these approximately 90% were pure
CNS manifestations. The most frequent NPSLE manifestations were headache (28.3%),
mood disorders (20.7%), cognitive dysfunction (19.7%), seizures (9.9%), and cerebrovascular
disease (8.0%). Epidemiological studies that excluded non-specific, minor CNS-symptoms,
such as mild cognitive dysfunction, headache, mild depression, and anxiety, demonstrated
a lower prevalence of NPSLE. Thus, one may suggest a new approach to defining NPSLE
manifestations. This approach will address major manifestations that may serve as
criteria and minor ones that are closely related to SLE but are less specific (for
example, head ache, anxiety, mild memory loss, etc.).

The complex pathophysiology of NPSLE

The development of NPSLE in a specific individual depends on genetic, environmental,
and hormonal factors. Despite decades of research our understanding of NPSLE remains
limited; however, several pathogenic pathways were identified and linked to specific
clinical manifestations such as antibody-mediated neurotoxicity, vasculopathy due
to anti-phospholipid (aPL) antibodies and other mechanisms, cytokine-induced neurotoxicity,
and loss of neuroplasticity (Figure 1).

Figure 1. Proposed pathogenesis of neuropsychiatric lupus. Auto-antibodies enter the brain causing neuronal damage, including impaired neuroplasticity
and synaptic transition. In order to reach the brain, the blood–brain barrier must
be transiently breached by external (for example, infection) or internal (for example,
metabolic derangement, cytokines) triggers. Vascular injury can be antibody mediated
by aPL antibodies or via accelerated classical atherosclerosis. aPL, Anti-phospholipid
antibodies; BBB, Blood brain barrier; RiboP, Ribosomal-P; NMDAR, NMDA receptor. The
authors are responsible for designing the figure above.

Vasculopathy

While only a minority of NPSLE patients have evidence of frank vasculitis on imaging
or histopathology, a small vessel thrombotic-vasculopathy has been the predominant
histopathological abnormality in brains of NPSLE patients at autopsy 6]. This small vessel vasculopathy is usually non-inflammatory, and its correlation
with clinical manifestations is not clear do date. It is presumed that the vascular
damage to the CNS in NPSLE is due to anti-phospholipid syndrome-related vasculopathy
or penetration of other autoantibodies through a damaged blood brain barrier (BBB),
immune complex and complement activation, cardiac emboli caused by Libman-Zachs endocarditis,
and other valvular abnormalities, vasculitis, or accelerated atherosclerosis.

Autoantibodies

The fact that numerous autoantibodies are detected in SLE patients, and particularly
in NPSLE, as well as the association between specific autoantibodies and certain manifestations
suggest that their presence is linked directly to pathogenesis 5],7],8]. More than 20 autoantibodies have been linked to NPSLE 9].The identification of pathogenic autoantibodies may serve as a possible drug target
in the future. A few are discussed below.

Anti-ribosomal-P antibodies

The presence of anti-ribosomal-P antibodies in NPSLE patients was first brought up
by Bonfa et al. 10] and later in numerous cohorts of NPSLE patients 11]. Nevertheless, other reports have failed to confirm this relationship 12]. A recent meta-analysis suggested that anti-ribosomal-P antibodies are specifically
related to psychosis in NPSLE 10]. Several studies demonstrated the ability of anti-ribosomal-P antibodies to bind
neuronal antigens, penetrate neuronal cells, and inhibit protein synthesis 13]-15]. Several autoantigens are suspected to interact with anti-ribosomal-P antibodies;
however, these interactions are yet to be confirmed. Recently, it was demonstrated
that anti-ribosomal-P may interact with neuronal surface-P antigen on the surface
of hippocampal neurons, leading to neuronal apoptosis 16]. In this animal study, intravenous injected anti-ribosomal P was able to reach the
hippocampus and cause memory impairment when the BBB was breached 16]. We recently demonstrated the binding to and penetration of anti-ribosomal-P antibodies
into rat hippocampal and human neuronal cells [Kivity et al. submitted for publication].
Furthermore, in our studies, anti-ribosomal-P antibodies bonded to a neuroplasticity
protein termed the growth associated protein-43. The binding of anti-ribosomal-P antibody
to murine brain tissue was inhibited by the presence of this protein, thus suggesting
that it may serve as an auto-antigen of anti-ribosomal-P antibodies in mice [Kivity
et al. submitted for publication].

The anti-DNA/NR2 antibodies

While the presence of anti-DNA antibodies correlates with SLE clinical manifestations,
especially glumerulonephritis and disease activity, its relationship to brain disease
is less clear. Diamond et al.17] demonstrated that anti-DNA can recognize a specific sequence (‘DWEYS’) contained
in the N-methyl-D-aspartate (NMDA) receptors NR2a and NR2b. Passive transfer of anti-DNA/NR2
antibodies causes neuronal apoptosis. In addition, active immunization with the DWEYs
followed by breaching of the BBB with lipopolysaccharide caused hippocampal neuron
damage coupled with memory loss 18]. These anti-DNA/NR2 antibodies can be detected in the serum and cerebrospinal fluid
(CSF) of 25 to 50% of SLE patients and some studies have found a correlation between
their blood levels and NPSLE symptoms 17]. Patients with the severe form of diffuse-NPSLE (acute confusional state) demonstrate
exceptionally high levels of anti-NR2 antibodies in the CSF accompanied by significant
BBB damage 19]. Murine studies demonstrated that at low concentration, NMDA receptor-specific antibodies
alter neural synaptic transmission, whereas at high concentration they induce neuronal
death, this may explain why cognitive dysfunction is transient in some patients and
permanent in others 20].

Anti-DNA/16–6 idiotype

The 16–6 idiotype (Id) was originally a monoclonal antibody directed against human
single-stranded-DNA. Over the years, the 16–6 Id has been detected in up to 30% of
lupus patients and was found to correlate with disease activity 21]. The anti-DNA/16–6 Id is related to NPSLE symptoms and can bind to human brain tissue
ex vivo21]. Intra-cerebro-ventricular injection of anti-DNA/16–6 Id was found to cause histological
changes in the hippocampus and amygdala as well as behavioral and cognitive functions
in mice 22].

Anti-phospholipid/anticardiolipin

Anti-phospholipid (aPL) autoantibodies are directed against epitopes of anionic phospholipids
or phospholipid-binding proteins (for example, B2Gp1). These antibodies are the most
studied in NPSLE, yet their pathogenesis is not clear. Their net effect, however,
is activation of coagulation pathways such as interference of fibrinolysis and natural
anticoagulants (for example, protein C and S), endothelial cell activation, complement
activation, platelet activation, and more 23]. SLE patients with secondary anti-phospholipid syndrome are prone to focal neurological
manifestations such as stroke, transverse myelitis, and chorea, as well as seizures,
migraine, and cognitive impairments 23].

Anti-GABA

A recent study demonstrated high levels of novel autoantibodies to GABA (B1 and B2)
receptors in sera and CSF of NPSLE patients 24].

Blood brain barrier (BBB) disruption

In order to enable auto-antibodies to penetrate the brain and cause their pathogenic
effect, the BBB must be breached. Different environmental factors, such as infection,
stress, and ischemia, mediated by inflammatory cytokines, may damage the BBB in different
anatomical sites, thus further contributing to the variety of neuropsychiatric symptoms.
Anti-ribosomal-P and anti-NR2 antibodies can induce the production of pro-inflammatory
cytokines, such as interleukin (IL)-6 and IL-8, by monocytes or endothelial cells.
These cytokines may cause inflammation of the BBB, further allowing the entrance of
auto-antibodies to the brain 25],26]. Recently, it was suggested that TWEAK/Fn14 signaling has a role in compromising
the integrity of the BBB in lupus 27].

Cytokines

Cytokines, such as IL-2, IL-10, interferon (IFN)-?, and IFN-?, are found to be elevated
in the serum of NPSLE patients. Elevation of cytokines in the CSF is also detected
in NPSLE, perhaps produced by infiltrating immune cells or local glial cells. The
role of cytokines and chemokines as mediator of disease as well as target for therapy
is yet to be determined 28].

Murine models – a platform for NPSLE research

SLE murine models can be differentiated into genetically designed strains that develop
a spontaneous lupus-like autoimmune disease or those induced by adjuvant or other
methods in naïve mice. Genetically prone strains are characterized by varying proportions
by autoantibody production, circulating immune complexes, complement consumption,
and clinical manifestations such as glomerulonephritis. These strains include the
NZB/NZWF1, MRL/lpr, NZM2410, and BXSB mice 29]. The most extensively studied strains are the MRL/lpr and NZB/NZW F1. The MRL/lpr
strain develops a progressive lupus-like disease due to a molecular defect in the
FAS gene, which is expressed in B and T lymphocytes. This leads to defective apoptosis,
thus causing autoimmunity. The most prominent neuropsychiatric manifestation of the
MRL/lpr mouse is depressive-like behavior, which can be assessed by the force swimming
and anhedonia tests at 5 weeks 30]. Anti-depressants, and more interestingly, immunosuppressants were found to reduce
depression-like behavior as well as the other SLE symptoms of this model 31]. However, there is less consistency regarding anxiety and cognitive impairment in
the MRL/lpr mice 29],31]. MRL/lpr mice produce several autoantibodies (anti-ribosomal, anti-phospholipid,
and anti-nucleosome) and cytokines in the serum or CSF that may correlate with neuropsychiatric
symptoms 31]. Spontaneous brain morphological alterations are also demonstrated in this strain
32]. A role for the TWEAK/fn4 pathway in the pathogenesis of neuropsychiatric symptoms
was suggested in MRL/lpr mice 33]. In addition, it is suggested that patterns of serum antibody binding to peptide
microarrays (immune-signaturing) can predict and diagnose neuropsychiatric manifestations
in MRL/lpr mice 34]. The NZB/NZWF1 is the F1 hybrid strain of a cross between New Zealand Black and New
Zealand White mice. It is the first and most studied spontaneous SLE-like mouse model.
This mice strain develops a severe lupus-like disease manifested at 5 to 6 months
by hyperactive B and T cells, autoantibodies against nuclear antigens, defective clearance
of immune complexes, and glomerulonephritis leading to death. A much more limited
number of studies intended to evaluate NPSLE were done in this strain, especially
due to the severity of clinical disease, its increased risk of developing inherited
brain anomalies, and a relatively late onset disease.

Clinical manifestations; case definitions (1–12)

The most frequent NPSLE manifestations are headaches, psychiatric disorders (depression
and anxiety), and cognitive dysfunction. Neuropsychiatric symptoms can be among the
earliest manifestations of SLE, and some reports suggest up to 40% of neuropsychiatric
symptoms appear during the first year of SLE diagnosis 7]. Caucasian ethnicity and older age are associated with shorter time to neuropsychiatric
damage according to the LUMINA study 35]. NPSLE symptoms can be a devastating manifestation of SLE, and a recent study demonstrated
a standard mortality ratio of 9.5, markedly with acute confessional syndrome 36]. NPSLE-CNS case definitions are discussed below:

1. Although headaches were once considered one of most common manifestations of NPSLE,
several studies, including a meta-analysis, have more recently concluded that the
rate of headaches among SLE patients was not significantly higher than it was in the
normal population. In addition, no particular mechanism was found to be responsible,
and headaches were not associated with general SLE disease activity, treatment, or
a specific autoantibody 37],38]. Therefore, it has been suggested that headaches should not be regarded as a major
NPSLE symptom unless they are intractable to treatment.

2. Seizures, generalized or focal, may develop in 10 to 20% of SLE patients 39], and tend to occur early in its course 40], especially in SLE patients with African ethnicity 41]. Generalized seizures tend to relate to disease activity while focal seizures can
occur at any stage of the disease. It is also crucial to exclude secondary causes
for seizures.

3. The incidence of stroke and transient ischemic attacks is elevated among SLE patients
42]. Cerebrovascular disease in SLE is strongly related to the presence of aPL antibodies
43], accelerated atherosclerosis 44], cardio-embolism due to heart valvular abnormalities, and Libman-Sacks endocarditis
45].

4. Clinical evidence of demyelination in NPSLE is reported in approximately 0.3% of
cases. Demyelination is one of the most poorly understood and studied NPSLE symptoms,
and can be a clinically isolated syndrome, may overlap with another CNS demyelinating
syndrome (for example, multiple sclerosis (MS)), be related to drugs, and, in some
cases, the diagnosis can be made only after long follow-up 46]. However, it should be noted that up to 60% of NPSLE patients may have oligoclonal
bands in their CSF, and evidence suggesting demyelination on imaging is not rare 5]. On the other hand, autoantibodies, such as aPL antibodies, may be detected in patients
with pure MS 47].

5. Transverse myelitis prevalence in SLE is approximately 1.5%. Several studies link
transverse myelitis-SLE with aPL antibodies 48], thus suggesting spinal cord necrosis due to thrombosis as an etiology. In some cases,
an overlap with Devic’s syndrome with the presence of anti-NMO antibodies is suspected.
In others, transverse myelitis may convert to definite MS.

6. Chorea is the most common movement disorder in SLE and appears in 2 to 3% of patients
49],50] and even in a higher percentage in children, while Parkinsonism, ataxia, and hemiballismus
are relatively rare. Chorea usually presents during the first years of SLE, and is
accompanied by aPL antibodies in up to 92% of cases 51],52]. It has been suggested that these antibodies cross the BBB, bind to neuronal antigens,
and induce this symptom 53]. Standard brain magnetic resonance imaging (MRI) has failed to demonstrate significant
changes in choreic NPSLE patients 54], while functional imaging suggested hyperactivity in the basal ganglia 49].

7. Aseptic meningitis can be a manifestation of active SLE. Other causes of aseptic
meningitis, such as infections, medication, and malignancy, should be excluded.

8. Cognitive impairment is highly prevalent among lupus patients, ranging from 20
to 80% 5],55]. Cognitive impairment does not seem to be directly attributable to disease activity,
disease burden, or corticosteroid therapy 56].

The distinction between functional and organic causes is the most difficult in the
case of psychiatric disorders 57].

9. Depression is the most common mood disorder in NPLSE, and its lifetime prevalence
may reach 65% 58], while mania is much less common. A recent study concluded that depression in SLE
is linked to several factors of which the usage of high dose prednisone (20 mg or
higher) was found to be the most significant independent factor, while global disease
activity was not 59]. Other contributing factors were recent SLE diagnosis, non-Asian ethnicity, cutaneous
disease, and longitudinal myelitis. These results may further support the notion that,
at least for some patients, SLE related depression is associated with adverse events
of therapy rather than with disease activity and may encourage clinicians to reduce
prednisone doses or avoid its use 59]. An association of depression and specific antibodies directed at ribosomal-P, NMDA
receptor, and other neuronal epitopes have been suggested 9],60].

10. Anxiety disorders are also common and can affect up to 40% of patients. Higher
anxiety and young age are risk factors for depression 61].

11. Organic psychosis can affect 2 to 11% 62],63] of SLE patients. In approximately 60% of these, it tends to be the presenting SLE-symptom
63]. SLE psychosis usually correlates with SLE activity and responds to immunosuppressive
therapy. The differential diagnosis is corticosteroid-induced psychosis, and its prevalence
in SLE was not found to be higher than in other autoimmune diseases 64].

12. Acute confusional state is a diffuse neurological dysfunction that manifests as
a fluctuating level of consciousness and disorientation and is equivalent to the term
delirium in the DSM-IV. Due to its rather vague definition, its prevalence is difficult
to estimate, ranging from 0 to 7% 65].

Other CNS manifestations that are not defined as case definitions include reversible
posterior leukoencephalopathy syndrome, an increasingly recognized condition in SLE
that manifests with a rapid onset of headaches, hypertension, seizures, and altered
mental states. Typical neuro-imaging reveals posterior cerebral white-matter hyper-intensities.
Prognosis is excellent with proper blood pressure and seizure control.

Olfactory impairments

SLE patients, especially those with active disease or CNS manifestations have been
shown to suffer from olfactory impairments 66]. Mice injected with anti-ribosomal-P antibodies intra-cerebra-ventricularily exhibit
impaired olfactory function 67], as well as MRI alterations in olfactory brain regions 68].

Peripheral nervous system manifestations

Peripheral nervous system manifestations affect approximately 10 to 15% of NPSLE cases,
and seven are considered in the 1999 ACR-NPSLE case definitions (Box 1). The majority
manifest as peripheral neuropathy 69], which includes mono or poly-neuropathy, cranial-neuropathy, inflammatory demyelinating
poly-radiculoneuropathy, and plexopathy. A recent finding is that 17% of SLE-related
peripheral neuropathies are small-fiber neuropathy 70]. Small-fiber neuropathies can cause severe burning pain by targeting unmyelinated
C fibers and thinly myelinated A fibers. The diagnosis can be supported by skin biopsy
that demonstrates damage to the dorsal root ganglia and distal axons. Other peripheral
nervous system manifestations are autonomic disorders and myasthenia gravis.

Diagnosis and imaging of NPSLE

The diagnosis of NPSLE may resemble the assembly of a puzzle: a clinician should first
diagnose SLE, and then exclude non-SLE inter-current illness, medication side effects,
and psychosocial- or functional-related conditions. It is important to note also that
the manifestations of NPSLE might overlap the neuropsychiatric manifestations of Sjögren’s
syndrome and aPL syndrome as well as other autoimmune diseases. Autoantibodies are
central for the diagnosis of SLE; however, note that the prevalence of anti-nuclear
antibodies in healthy subjects may reach 20% at certain ages 71], and many non-SLE patients with mild CNS symptoms, such as weakness or headache,
might have weakly positive anti-nuclear antibodies testing. For patients with established
SLE, several autoantibodies were found to correlate with neuropsychiatric symptoms:
aPL antibodies with stroke and vascular dementia, seizures, chorea, headache, and
transverse myelitis; anti-ribosomal-P and depression or psychosis; anti-neuronal with
cognitive dysfunction and depression; anti-ganglioside antibodies with migraine, acute
confusional state, depression, and peripheral neuropathy 72]; yet, none of these antibodies can serve as a definite marker of NPSLE.

Cerebrospinal fluid

CSF analysis in NPSLE patients may be innocent, and thus non-contributory. In some
cases, such as vasculitis, aseptic meningitis, and transverse myelitis, it may have
a high yield in diagnosis. Several reports demonstrated immunological markers such
as anti-DNA antibodies, oligoclonal banding, immune complexes, IL-6, and markers of
B-cell activation in the CSF of NPSLE patients 73]-75].

Psychological testing

Neuropsychological testing may help to differentiate between functional and non-functional
disease, but these tests are prolonged and complicated and, thus, are almost never
routinely performed. The 1999 ACR-NPSLE committee proposed a relatively short (1 hour)
battery of neuropsychological tests for use when NPSLE is suspected (Table 1), which is shorter than the 4 to 5 hour comprehensive batteries used before. This
was validated and found reliable 76].

Table 1. Neuropsychological testing in neuropsychiatric lupus syndrome (NPSLE) – The ACR 1-hour battery proposal

Biomarkers in NPSLE

In order to better screen and monitor NPSLE treatment, there is an ongoing search
for biomarkers, other than autoantibodies, cytokines, and chemokines, in this patient
population. Intra-thecal levels of plasminogen activator inhibitor 1 and MMP-9 were
found to correlate with NPSLE activity 77]. It was recently demonstrated that the combination of blood levels of several brain-reactive
proteins (neutrophil gelatinase-associated lipocalin, S100B, and S100A8/9) with anti-NR2
and anti-ribosomal-P antibody levels is associated with cognitive impairment in childhood-onset
NPSLE patients 78].

Imaging

Several imaging modalities have enhanced our ability to investigate NPSLE; others
appear promising in the near future and need further research and validation.

Computerized tomography (CT)

CT is used mainly in emergency settings to exclude focal abnormalities such as infarcts,
hemorrhage, and tumors. Chronic conditions which can be demonstrated are cortical
atrophy and calcifications.

Magnetic resonance imaging (MRI)

MRI is widely used in NPSLE because it is sensitive, relatively available, and can
exclude other neurological conditions. However, more than half of patients diagnosed
with NPSLE have a normal MRI of the brain 79], this is much less so as the disease progresses and worsens. MRI is mostly sensitive
to focal findings such as cerebrovascular disease and myelitis (80 to 90%), while
its sensitivity decreases for white matter lesions, gray matter lesions, and cerebral
atrophy 80]. It should be noted that the latter findings can be found in non-SLE neuropsychiatric
patients as well.

Other imaging modalities

Single photon emission computed tomography (SPECT) provides an estimate of regional
cerebral blood flow and neuronal integrity and was thought to be more sensitive than
MRI for the evaluation of NPSLE by some researchers. However, studies were inconsistent.
Positron emission tomography–CT measures radio-labeled oxygen and glucose uptake by
the brain. Several studies demonstrated an alteration in cerebral metabolism in NPSLE
81]. However, this modality is expensive, difficult to perform, and has not yet been
proven to significantly contribute to an NPSLE work up 33]. A few studies have shown defective brain activity during activity such as memory
tasks using functional MRI. In a recent study, childhood-onset NPSLE patients with
cognitive impairment, demonstrated differential activation of functional neuronal
networks during functional MRI tasks, suggesting this modality can serve as an imaging
biomarker 80]. Magnetic resonance spectroscopy (MRS) is a relatively new modality that can non-invasively
quantify several metabolites in brain tissue (for example, N-acetyl aspartate) 82],83]. Several metabolites have been used to examine NPSLE, however, these changes are
not specific to SLE and might be present in other progressive diseases of the brain
such as Alzheimer’s disease and MS 84]. MRS is not currently recommended for NPSLE patients although, in the future, it
may help monitor and diagnose NPSLE.

Treatment options for neuropsychiatric lupus

Treatment of NPSLE may combine therapy directed at an underlying mechanism such as
autoantibody mediated damage or a hyper-coagulable state, while controlling symptoms
with anti-epileptic, anti-depressive, anti-neuropathy, and other medications. Currently,
no randomized controlled studies have been done to verify therapies or protocols for
specific NPSLE manifestations. Hence, treatment regimens are based on expert recommendations,
case studies, and small controlled trials. NPSLE therapy should be individualized
based on suspected mechanisms (for example, the presence of specific antibodies or
evidence of thrombosis), severity of symptoms, expected morbidity, time from onset
of symptoms, reversibility, response to prior therapies, and effect on quality of
life. Symptomatic therapy alone may be considered for mild NPSLE, especially when
further damage is not expected. For instance, depression, headaches, and recurrent
seizures do not commonly represent active SLE disease, but rather associated conditions
or sequel of previous event (for example, post-stroke seizures). In contrast, if severe/new
onset disease is diagnosed, especially in the presence of high SLE activity, immunosuppressant
and/or directed therapy are required to control the autoimmune process and avoid further
damage. Evidence exists for off-label aggressive intervention for acute NPSLE such
as aseptic meningitis, myelitis, neuropathy, and psychosis. In general, treatment
options for these severe and acute neuro-psychiatric symptoms are similar to those
utilized for other major organ involvement in SLE or for non-SLE CNS vasculitis. These
include non-specific immunosuppression, specific immune modulation mainly targeted
at the humoral arm of the immune system, and/or anti-coagulation. The most studied
immunosuppressive modality is the use of systemic gluco-corticosteroids (GC) that
may lead to a beneficial response in 60 to 75% of patients. High doses of GC are almost
universally utilized, and for severe signs or symptoms, ‘pulse therapy’ with very
high doses of GC (for example, IV 1 g solomedrol/day for 3 to 5 days) followed by
oral therapy (for example, prednisone 1 mg/kg/day) have been extensively used. Although
emotional instability, mood swings (for example, depression), disfigurement, and various
other adverse events are common in SLE patients treated with GC, and may interfere
with the appropriate appraisal of disease, it is still the most effective immediate
therapy available.

In many moderate to severe NPSLE presentations, additional immune suppressants are
required to control the disease and enable GC withdrawal. Cyclophosphamide (CYC) is
probably the most used immunosuppressant for severe NPSLE. In a controlled clinical
trial 85], the addition of IV CYC to methylprednisolone was superior to therapy with methylprednisolone
pulses alone for 32 patients with acute severe NPSLE (refractory seizures, cranial
or peripheral neuropathy, optic neuritis, transverse myelitis, brainstem disease,
and coma). All patients were treated with prednisone between pulses. Due to the effects
of CYC, ovarian or sperm preservation should be considered. In another study, 37 out
of 60 patients with NPSLE were treated with low doses of IV CYC (200 to 400 mg per
month). Treated patients had a statistically significant improvement when compared
to the control group that was treated with prednisone and plaquenil only 86]. Several reports describe successful use of azathioprine and mycophenolate mofetil
as second line therapy 87] and for ‘maintenance therapy’ in order to avoid prolonged exposure to high dose steroids
or as a substitute for prolonged therapy with CYC. For refractory disease, and particularly
NPSLE which is considered to be induced by autoantibodies, therapy with anti-B cell
therapy (rituximab), plasma exchange, or intravenous immunoglobulins (IVIG) may be
considered.

Anti-B cell therapies

B-lymphocytes play a central role in lupus pathogenesis, therefore, drugs such as
anti-CD20 monoclonal antibodies (for example, Rituximab), which directly affect several
B cell populations, were suggested for refractory disease. In a recent systematic
review, rituximab was beneficial in 73 to 100% of 38 patients with refractory NPSLE;
however, relapse rates were high 88], suggesting that repeated therapy with rituximab may be warranted. The selection
and survival of B cells are controlled by a variety of signals, including those provided
by the longevity factor, B cell activating factor. Belimumab is a fully human monoclonal
antibody directed against B cell activating factor that has recently been proven to
be a promising therapy for SLE. Note that in both randomized controlled studies with
this new biological drug, patients with active NPSLE were excluded 89]. However, post hoc analysis performed for both phase III trials (BLISS-52 and BLISS-76) demonstrated
clinical improvements in organ systems with a low prevalence (?16%) at baseline, including
the CNS 90].

Therapies directed at reducing auto-antibodies with plasmapheresis or therapy directed
at specific cytokines may also be considered. Plasmapheresis, added as an adjunct
therapy for chorea or myelitis in NPSLE patients has been found to be effective. In
one retrospective study, plasmapheresis was added to IV CYC and GC and led to a complete
remission in 54% of 10 NPSLE patients 91]. In recent years, we successfully treated several patients presenting with acute
severe NPSLE with plasmapheresis. The role of IVIG for NPSLE had been studied in a
small number of patients. In one study of 9 NPSLE patients with mood swings and cognitive
disorders, long-term therapy with high dose IVIG was found to be beneficial and safe
92].

Anti-aggregation/anticoagulation therapy

There is no question that thrombosis plays a major role in the pathogenesis of NPSLE,
especially in patients with aPL antibodies. This is typically indicated when manifestations
are focal, and both clinical and radiographic evaluation support ischemic or thrombotic
events 93]. Therefore, the current recommendation is to treat patients with SLE who are seropositive
to aPL antibodies with anti-aggregants as primary prevention, while the addition of
anticoagulants is usually reserved for secondary prevention 94].

Last but not least, management of precipitating factors is imperative and includes
control of hypertension, infection, metabolic abnormalities, valvular disease, and
adverse drug effects 93].

Future studies

Specific anti-IL-6 drugs have been developed in the last decade and studied extensively
in several autoimmune conditions. NPSLE was linked with high levels of IL-6 as well
as with BBB disruption by the TWEAK/Fn14 pathway. Hence, therapies directed at these
mediators may be of value also in NPSLE, although clinical studies are still lacking.